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1
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Wang S, Xu R, Li G, Liu S, Zhu J, Gao P. A Plasma Proteomics-Based Model for Identifying the Risk of Postpartum Depression Using Machine Learning. J Proteome Res 2025; 24:824-833. [PMID: 39772732 PMCID: PMC11812005 DOI: 10.1021/acs.jproteome.4c00826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 11/28/2024] [Accepted: 12/26/2024] [Indexed: 01/11/2025]
Abstract
Postpartum depression (PPD) poses significant risks to maternal and infant health, yet proteomic analyses of PPD-risk women remain limited. This study analyzed plasma samples from 30 healthy postpartum women and 30 PPD-risk women using mass spectrometry, identifying 98 differentially expressed proteins (29 upregulated and 69 downregulated). Principal component analysis revealed distinct protein expression profiles between the groups. Functional enrichment and PPI analyses further explored the biological functions of these proteins. Machine learning models (XGBoost and LASSO regression) identified 17 key proteins, with the optimal logistic regression model comprising P13797 (PLS3), P56750 (CLDN17), O43173 (ST8SIA3), P01593 (IGKV1D-33), and P43243 (MATR3). The model demonstrated excellent predictive performance through ROC curves, calibration, and decision curves. These findings suggest potential biomarkers for early PPD risk assessment, paving the way for personalized prediction. However, limitations include the lack of diagnostic interviews, such as the Structured Clinical Interview for DSM-V (SCID), to confirm PPD diagnosis, a small sample size, and limited ethnic diversity, affecting generalizability. Future studies should expand sample diversity, confirm diagnoses with SCID, and validate biomarkers in larger cohorts to ensure their clinical applicability.
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Affiliation(s)
- Shusheng Wang
- Department
of Traditional Chinese Medicine, Jinshan
Hospital, Fudan University, Shanghai 201508, China
| | - Ru Xu
- Department
of Traditional Chinese Medicine, Jinshan
Hospital, Fudan University, Shanghai 201508, China
| | - Gang Li
- Department
of Laboratory Medicine, Jinshan Hospital,
Fudan University, Shanghai 201508, China
| | - Songping Liu
- Department
of Obstetrics and Gynecology, Jinshan Hospital,
Fudan University, Shanghai 201508, China
| | - Jie Zhu
- Department
of Rehabilitation, Jinshan Hospital, Fudan
University, Shanghai 201508, China
| | - Pengfei Gao
- Department
of Traditional Chinese Medicine, Jinshan
Hospital, Fudan University, Shanghai 201508, China
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2
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Zervou Z, Bevers MSAM, Wyers CE, Bruggenwirth HT, Demirdas S, van den Bergh JP, Zillikens MC. Bone microarchitecture and strength in men and women with PLS3 gene variants assessed with HR-pQCT. J Bone Miner Res 2025; 40:241-250. [PMID: 39658012 DOI: 10.1093/jbmr/zjae186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 10/07/2024] [Accepted: 12/05/2024] [Indexed: 12/12/2024]
Abstract
X-linked osteoporosis, caused by PLS3 genetic variants, is a rare bone disease, clinically affecting mainly men. Limited data are available on bone microarchitecture and genotype-phenotype correlations in this disease. Our aims were to assess bone microarchitecture and strength in adults with PLS3 variants using high-resolution peripheral quantitative computed tomography (HR-pQCT) and to explore differences in the phenotype from HR-pQCT between PLS3 variants. HR-pQCT scans were obtained from the distal radius and tibia of 13 men and 3 women with PLS3 variants. Results were compared with age- and sex-matched controls from a normative dataset from literature and expressed as Z-scores. Median age was 46 yr for men and 48 yr for women. In men, total bone area was large (median Z-score: 1.33 radius; 1.46 tibia) due to a large trabecular area (+1.73 radius; +1.87 tibia), while the cortical area was small (-2.61 radius; -2.84 tibia). Total volumetric bone mineral density (BMD) was low due to low trabecular (-3.46 radius; -3.37 tibia) and cortical BMD (-2.87 radius; -2.26 tibia). Regarding bone microarchitecture, the largest deviations were found in trabecular number (-2.18 radius; -1.64 tibia), trabecular separation (+2.32 radius; +1.65 tibia), and cortical thickness (-2.99 radius; -2.46 tibia), whereas trabecular thickness and cortical porosity were normal (-0.36 and -0.58 radius; 0.09 and -0.79 tibia). Additionally, failure load was low (-2.39 radius; -2.2 tibia). Results in the women deviated less from normative data. Men with frameshift/nonsense variants seemed to have more deviant trabecular and cortical microarchitecture and strength, at both scan locations, than those with missense/in-frame insertion variants. In conclusion, HR-pQCT provides valuable insights into bone area, BMD, microarchitecture, and strength in adults with PLS3 variants and can be used to explore genotype-phenotype relationships. Longitudinal analyses in larger groups are needed to study the natural course of the disease and treatment effects.
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Affiliation(s)
- Zografia Zervou
- Department of Internal Medicine, Erasmus MC Bone Center, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
| | - Melissa S A M Bevers
- Department of Internal Medicine, VieCuri Medical Center, Tegelseweg 210, 5912 BL, Venlo, The Netherlands
- NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Minderbroedersberg 4-6, 6211 LK, Maastricht, The Netherlands
- Department of Biomedical Engineering, Eindhoven University of Technology, Groene Loper 3, 5612 AE, Eindhoven, The Netherlands
| | - Caroline E Wyers
- Department of Internal Medicine, VieCuri Medical Center, Tegelseweg 210, 5912 BL, Venlo, The Netherlands
- NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Minderbroedersberg 4-6, 6211 LK, Maastricht, The Netherlands
- Department of Internal Medicine, Subdivision Rheumatology, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands
| | - Hennie T Bruggenwirth
- Department of Clinical Genetics, Erasmus MC, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
| | - Serwet Demirdas
- Department of Clinical Genetics, Erasmus MC, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
| | - Joop P van den Bergh
- Department of Internal Medicine, VieCuri Medical Center, Tegelseweg 210, 5912 BL, Venlo, The Netherlands
- NUTRIM Institute of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Minderbroedersberg 4-6, 6211 LK, Maastricht, The Netherlands
- Department of Internal Medicine, Subdivision Rheumatology, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands
| | - M Carola Zillikens
- Department of Internal Medicine, Erasmus MC Bone Center, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
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3
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Shi T, Zhou Z, Xiang T, Suo Y, Shi X, Li Y, Zhang P, Dai J, Sheng L. Cytoskeleton dysfunction of motor neuron in spinal muscular atrophy. J Neurol 2024; 272:19. [PMID: 39666039 PMCID: PMC11638312 DOI: 10.1007/s00415-024-12724-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 11/12/2024] [Accepted: 11/15/2024] [Indexed: 12/13/2024]
Abstract
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deletions or mutations of survival of motor neuron 1 (SMN1) gene. To date, the mechanism of selective cell death of motor neurons as a hallmark of SMA is still unclear. The severity of SMA is dependent on the amount of survival motor neuron (SMN) protein, which is an essential and ubiquitously expressed protein involved in various cellular processes including regulation of cytoskeletal dynamics. In this review, we discuss the effect of SMN ablation on cytoskeleton organization including actin dynamics, growth cone formation, axonal stability, neurite outgrowth, microtubule stability, synaptic vesicle dynamics and neurofilament protein release in SMA. We also summarized a list of critical proteins such as profilin-2 (PFN2), plastin-3 (PLS3), stathmin-1 (STMN1), microtubule-associated protein 1B (MAP1B) and neurofilament which play an important role in modulating cytoskeleton in SMA. Our aim is to highlight how cytoskeletal defects contribute to motor neuron degeneration in SMA disease progression and concentrating on cytoskeleton dynamics may be a promising approach to develop new therapy or biomarker.
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Affiliation(s)
- Tianyu Shi
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Zijie Zhou
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Taiyang Xiang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Yinxuan Suo
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Xiaoyan Shi
- Department of Neurology, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu, China
| | - Yaoyao Li
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Peng Zhang
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215004, Jiangsu, China
| | - Jun Dai
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215004, Jiangsu, China.
| | - Lei Sheng
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215004, Jiangsu, China.
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4
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Sillence DO. A Dyadic Nosology for Osteogenesis Imperfecta and Bone Fragility Syndromes 2024. Calcif Tissue Int 2024; 115:873-890. [PMID: 38942908 PMCID: PMC11607092 DOI: 10.1007/s00223-024-01248-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 06/17/2024] [Indexed: 06/30/2024]
Abstract
In 2023 following extensive consultation with key stakeholders, the expert Nosology Working Group of the International Skeletal Dysplasia Society (ISDS) published the new Dyadic Nosology for Genetic Disorders of the Skeleton. Some 770 entities were delineated associated with 552 genes. From these entities, over 40 genes resulting in distinct forms of Osteogenesis Imperfecta (OI) and Bone Fragility and/or Familial Osteoporosis were identified. To assist clinicians and lay stake holders and bring the considerable body of knowledge of the matrix biology and genomics to people with OI as well as to clinicians and scientists, a dyadic nosology has been recommended. This combines a genomic co-descriptor with a phenotypic naming based on the widely used Sillence nosology for the OI syndromes and the many other syndromes characterized in part by bone fragility.This review recapitulates and explains the evolution from the simple Congenita and Tarda subclassification of OI in the 1970 nosology, which was replaced by the Sillence types I-IV nosology which was again replaced in 2009 with 5 clinical groups, type 1 to 5. Qualitative and quantitative defects in type I collagen polypeptides were postulated to account for the genetic heterogeneity in OI for nearly 30 years, when OI type 5, a non-collagen disorder was recognized. Advances in matrix biology and genomics since that time have confirmed a surprising complexity both in transcriptional as well as post-translational mechanisms of collagens as well as in the many mechanisms of calcified tissue homeostasis and integrity.
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Affiliation(s)
- David Owen Sillence
- Specialities of Genomic Medicine and Paediatrics and Adolescent Health, Children's Hospital Westmead, Sydney University Clinical School, Westmead, NSW, 2145, Australia.
- Department of Genetic Medicine, Honorary Emeritus Consultant, Westmead Hospital, Westmead, NSW, 2145, Australia.
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5
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Mancini M, Chapurlat R, Isidor B, Desjonqueres M, Couture G, Guggenbuhl P, Coutant R, El Chehadeh S, Fradin M, Frazier A, Goldenberg A, Guillot P, Koumakis E, Mehsen-Cêtre N, Rossi M, Schaefer É, Sigaudy S, Porquet-Bordes V, Fontanges É, Letard P, Edouard T, Javier RM, Cohen-Solal M, Funck-Brentano T, Collet C. Early-Onset Osteoporosis: Molecular Analysis in Large Cohort and Focus on the PLS3 Gene. Calcif Tissue Int 2024; 115:591-598. [PMID: 39316135 DOI: 10.1007/s00223-024-01288-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 09/01/2024] [Indexed: 09/25/2024]
Abstract
Osteoporosis is a skeletal disorder characterized by abnormal bone microarchitecture and low bone mineral density (BMD), responsible for an increased risk of fractures and skeletal fragility. It is a common pathology of the aging population. However, when osteoporosis occurs in children or young adults, it strongly suggests an underlying genetic etiology. Over the past two decades, several genes have been identified as responsible for this particular kind of considered monogenic early-onset osteoporosis (EOOP) or juvenile osteoporosis, the main ones being COL1A1, COL1A2, LRP5, LRP6, WNT1, and more recently PLS3. In this study, the objective was to characterize a large cohort of patients diagnosed with primary osteoporosis and to establish its diagnosis yield. The study included 577 patients diagnosed with primary osteoporosis and its diagnosis yield was established. To this end, next-generation sequencing (NGS) of a panel of 21 genes known to play a role in bone fragility was carried out. A genetic etiology was explained in about 18% of cases, while the others remain unexplained. The most frequently identified gene associated with EOOP is LRP5, which was responsible for 8.2% of the positive results (47 patients). As unexpected, 17 patients (2.9%) had a variant in PLS3 which encodes plastin 3. Alterations of PLS3 are associated with dominant X-linked osteoporosis, an extremely rare disease. Given the rarity of this disease, we focused on it. It was observed that males were more affected than females, but it is noteworthy that three females with a particularly severe phenotype were identified. Of these three, two had a variant in an additional gene involved in EOP, illustrating the probable existence of digenism. We significantly increase the number of variants potentially associated with EOOP, especially in PLS3. The results of our study demonstrate that molecular analysis in EOOP is beneficial and useful.
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Affiliation(s)
- Maxence Mancini
- Biochemistry and Molecular Genetics Department, Lariboisière Hospital, AP-HP, Paris, France
| | - Roland Chapurlat
- Rheumatology and Bone Pathology Department, Inserm UMR 1033, Université de Lyon, Edouard Herriot Hospital, HCL, Lyon, France
| | - Bertrand Isidor
- Medical Genetics Department, CHU de Nantes, Hôtel Dieu Hospital, Nantes, France
| | - Marine Desjonqueres
- Nephrology - Rheumatology - Dermatology Paediatric Department, Edouard Herriot Hospital, HCL, Lyon, France
| | - Guillaume Couture
- Endocrine, Bone Diseases and Genetics Unit, Rheumatology Department, Reference Centre for Rare Diseases of Calcium and Phosphate Metabolism, ERN BOND, OSCAR Network, University Hospital, RESTORE, INSERM U1301, Toulouse, France
| | | | - Régis Coutant
- Department of Paediatrics and Endocrinology, CHU d'Angers, Angers, France
| | - Salima El Chehadeh
- Medical Genetics Department, Institut de Génétique Médicale d'alsace, CHU de Strasbourg, Strasbourg, France
| | - Mélanie Fradin
- Clinical Genetics Department, CHU Rennes, Sud Hospital, Rennes, France
| | - Aline Frazier
- Rheumatology Department, Inserm 1132, Univsersité Paris-Cité, Lariboisière Hospital, AP-HP, Paris, France
| | - Alice Goldenberg
- Medical Genetics Department, Charles- Nicolle Hospital, CHU de Rouen, Rouen, France
| | - Pascaline Guillot
- Rheumatology Department, CHU de Nantes, Hôpital Hôtel Dieu, Nantes, France
| | | | | | - Massimiliano Rossi
- Medical Genetics Department, Edouard Herriot Hospital, HCL, Lyon, France
| | - Élise Schaefer
- Medical Genetics Department, Institut de Génétique Médicale d'alsace, CHU de Strasbourg, Strasbourg, France
| | - Sabine Sigaudy
- Medical Genetics Department, CHU de Marseille, Timone Hospital, Marseille, France
| | - Valérie Porquet-Bordes
- Endocrine, Bone Diseases and Genetics Unit, Reference Centre for Rare Diseases of Calcium and Phosphate Metabolism, ERN BOND, OSCAR Network, Paediatric Research Unit, Children's Hospital, Toulouse University Hospital, RESTORE, INSERM U1301, Toulouse, France
| | - Élisabeth Fontanges
- Rheumatology and Bone Pathology Department, Inserm UMR 1033, Université de Lyon, Edouard Herriot Hospital, HCL, Lyon, France
| | - Pauline Letard
- Medical Genetics Department, CHU de Poitiers, Poitiers, France
| | - Thomas Edouard
- Endocrine, Bone Diseases and Genetics Unit, Reference Centre for Rare Diseases of Calcium and Phosphate Metabolism, ERN BOND, OSCAR Network, Paediatric Research Unit, Children's Hospital, Toulouse University Hospital, RESTORE, INSERM U1301, Toulouse, France
| | - Rose-Marie Javier
- Rheumatology Department, CHU de Strasbourg, Hautepierre Hospital, Strasbourg, France
| | - Martine Cohen-Solal
- Rheumatology Department, Inserm 1132, Univsersité Paris-Cité, Lariboisière Hospital, AP-HP, Paris, France
| | - Thomas Funck-Brentano
- Rheumatology Department, Inserm 1132, Univsersité Paris-Cité, Lariboisière Hospital, AP-HP, Paris, France
| | - Corinne Collet
- Rare Disease Genomic Medicine Department, CHU Necker-Enfants Malades, INSERM UMR1163, Institut Imagine, Université Paris-Cité, Paris, France.
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6
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Schembri M, Formosa MM. Identification of osteoporosis genes using family studies. Front Endocrinol (Lausanne) 2024; 15:1455689. [PMID: 39502568 PMCID: PMC11534825 DOI: 10.3389/fendo.2024.1455689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/29/2024] [Indexed: 11/08/2024] Open
Abstract
Osteoporosis is a multifactorial bone disease characterised by reduced bone mass and increased fracture risk. Family studies have made significant contribution in unravelling the genetics of osteoporosis. Yet, most of the underlying molecular and biological mechanisms remain unknown prompting the need for further studies. This review outlines the proper phenotyping and advanced genetic techniques in the form of high-throughput DNA sequencing used to identify genetic factors underlying monogenic osteoporosis in a family-based setting. The steps related to variant filtering prioritisation and curation are also described. From an evolutionary perspective, deleterious risk variants with higher penetrance tend to be rare as a result of negative selection. High-throughput sequencing (HTS) can identify rare variants with large effect sizes which are likely to be missed by candidate gene analysis or genome-wide association studies (GWAS) wherein common variants with small to moderate effect sizes are identified. We also describe the importance of replicating implicated genes, and possibly variants, identified following HTS to confirm their causality. Replication of the gene in other families, singletons or independent cohorts confirms that the shortlisted genes and/or variants are indeed causal. Furthermore, novel genes and/or variants implicated in monogenic osteoporosis require a thorough validation by means of in vitro and in vivo assessment. Therefore, analyses of families can continue to elucidate the genetic architecture of osteoporosis, paving the way for improved diagnostic and therapeutic strategies.
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Affiliation(s)
- Marichela Schembri
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
| | - Melissa M. Formosa
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
- Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
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7
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Zhong W, Neugebauer J, Pathak JL, Li X, Pals G, Zillikens MC, Eekhoff EMW, Bravenboer N, Zhang Q, Hammerschmidt M, Wirth B, Micha D. Functional Insights in PLS3-Mediated Osteogenic Regulation. Cells 2024; 13:1507. [PMID: 39273077 PMCID: PMC11394082 DOI: 10.3390/cells13171507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 09/15/2024] Open
Abstract
Plastin-3 (PLS3) encodes T-plastin, an actin-bundling protein mediating the formation of actin filaments by which numerous cellular processes are regulated. Loss-of-function genetic defects in PLS3 are reported to cause X-linked osteoporosis and childhood-onset fractures. However, the molecular etiology of PLS3 remains elusive. Functional compensation by actin-bundling proteins ACTN1, ACTN4, and FSCN1 was investigated in zebrafish following morpholino-mediated pls3 knockdown. Primary dermal fibroblasts from six patients with a PLS3 variant were also used to examine expression of these proteins during osteogenic differentiation. In addition, Pls3 knockdown in the murine MLO-Y4 cell line was employed to provide insights in global gene expression. Our results showed that ACTN1 and ACTN4 can rescue the skeletal deformities in zebrafish after pls3 knockdown, but this was inadequate for FSCN1. Patients' fibroblasts showed the same osteogenic transdifferentiation ability as healthy donors. RNA-seq results showed differential expression in Wnt1, Nos1ap, and Myh3 after Pls3 knockdown in MLO-Y4 cells, which were also associated with the Wnt and Th17 cell differentiation pathways. Moreover, WNT2 was significantly increased in patient osteoblast-like cells compared to healthy donors. Altogether, our findings in different bone cell types indicate that the mechanism of PLS3-related pathology extends beyond actin-bundling proteins, implicating broader pathways of bone metabolism.
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Affiliation(s)
- Wenchao Zhong
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; (W.Z.); (G.P.)
- Department of Clinical Chemistry, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands;
- Amsterdam Movement Sciences, Tissue Function And Regeneration, 1081 HV Amsterdam, The Netherlands;
- Department of Temporomandibular Joint, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510060, China; (J.L.P.); (X.L.); (Q.Z.)
| | - Janine Neugebauer
- Institute of Human Genetics University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; (J.N.); (B.W.)
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
| | - Janak L. Pathak
- Department of Temporomandibular Joint, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510060, China; (J.L.P.); (X.L.); (Q.Z.)
| | - Xingyang Li
- Department of Temporomandibular Joint, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510060, China; (J.L.P.); (X.L.); (Q.Z.)
| | - Gerard Pals
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; (W.Z.); (G.P.)
- Amsterdam Movement Sciences, Tissue Function And Regeneration, 1081 HV Amsterdam, The Netherlands;
| | - M. Carola Zillikens
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 CE Rotterdam, The Netherlands;
| | - Elisabeth M. W. Eekhoff
- Amsterdam Movement Sciences, Tissue Function And Regeneration, 1081 HV Amsterdam, The Netherlands;
- Department Internal Medicine, Endocrinology and Metabolism, Amsterdam UMC Location Vrije Universiteit Amsterdam, Rare Bone Disease Center, 1081 HV Amsterdam, The Netherlands
- Amsterdam Reproduction and Development, 1105 AZ Amsterdam, The Netherlands
| | - Nathalie Bravenboer
- Department of Clinical Chemistry, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands;
- Amsterdam Movement Sciences, Tissue Function And Regeneration, 1081 HV Amsterdam, The Netherlands;
| | - Qingbin Zhang
- Department of Temporomandibular Joint, School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510060, China; (J.L.P.); (X.L.); (Q.Z.)
| | - Matthias Hammerschmidt
- Developmental Biology Unit, Institute of Zoology, University of Cologne, 50931 Cologne, Germany;
- Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany
| | - Brunhilde Wirth
- Institute of Human Genetics University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany; (J.N.); (B.W.)
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
- Center for Rare Diseases, University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany
| | - Dimitra Micha
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; (W.Z.); (G.P.)
- Amsterdam Movement Sciences, Tissue Function And Regeneration, 1081 HV Amsterdam, The Netherlands;
- Amsterdam Reproduction and Development, 1105 AZ Amsterdam, The Netherlands
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8
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Aliyeva L, Ongen YD, Eren E, Sarisozen MB, Alemdar A, Temel SG, Sag SO. Genotype and Phenotype Correlation of Patients with Osteogenesis Imperfecta. J Mol Diagn 2024; 26:754-769. [PMID: 39025364 DOI: 10.1016/j.jmoldx.2024.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 04/17/2024] [Accepted: 05/16/2024] [Indexed: 07/20/2024] Open
Abstract
Osteogenesis imperfecta (OI) is the most common inherited connective tissue disease of the bone, characterized by recurrent fractures and deformities. In patients displaying the OI phenotype, genotype-phenotype correlation is used to screen multiple genes swiftly, identify new variants, and distinguish between differential diagnoses and mild subtypes. This study evaluated variants identified through next-generation sequencing in 58 patients with clinical characteristics indicative of OI. The cohort included 18 adults, 37 children, and 3 fetuses. Clinical classification revealed 25 patients as OI type I, three patients as OI type II, 18 as OI type III, and 10 as OI type IV. Fifteen variants in COL1A1 were detected in 19 patients, 9 variants in COL1A2 (n = 19), 5 variants in LEPRE1/P3H1 (n = 7), 3 variants in FKBP10 (n = 4), 3 variants in SERPINH1 (n = 2), 1 variant in IFITM5 (n = 1), and 1 variant in PLS3 (n = 1). In total, 37 variants (18 pathogenic, 14 likely pathogenic, and 5 variants of uncertain significance), including 16 novel variants, were identified in 43 (37 probands, 6 family members) of the 58 patients analyzed. This study highlights the efficacy of panel testing in the molecular diagnosis of OI, the significance of the next-generation sequencing technique, and the importance of genotype-phenotype correlation.
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Affiliation(s)
- Lamiya Aliyeva
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey; Department of Medical Genetics, Atakent Hospital, Acibadem Health Group, Istanbul, Türkiye
| | - Yasemin Denkboy Ongen
- Department of Pediatric Endocrinology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Erdal Eren
- Department of Pediatric Endocrinology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Mehmet B Sarisozen
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey
| | - Adem Alemdar
- Department of Translational Medicine, Health Sciences Institute, Bursa Uludag University, Bursa, Türkiye
| | - Sehime G Temel
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey; Department of Histology and Embryology, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey; Department of Translational Medicine, Health Sciences Institute, Bursa Uludag University, Bursa, Türkiye.
| | - Sebnem Ozemri Sag
- Department of Medical Genetics, Faculty of Medicine, Bursa Uludag University, Bursa, Turkey.
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9
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An JY, Ma XN, Wen HL, Hu HD. Identification of key genes and long non‑coding RNA expression profiles in osteoporosis with rheumatoid arthritis based on bioinformatics analysis. BMC Musculoskelet Disord 2024; 25:634. [PMID: 39118036 PMCID: PMC11312199 DOI: 10.1186/s12891-024-07738-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 07/26/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Although rheumatoid arthritis (RA) is a chronic systemic tissue disease often accompanied by osteoporosis (OP), the molecular mechanisms underlying this association remain unclear. This study aimed to elucidate the pathogenesis of RA and OP by identifying differentially expressed mRNAs (DEmRNAs) and long non-coding RNAs (lncRNAs) using a bioinformatics approach. METHODS Expression profiles of individuals diagnosed with OP and RA were retrieved from the Gene Expression Omnibus database. Differential expression analysis was conducted. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) pathway enrichment analyses were performed to gain insights into the functional categories and molecular/biochemical pathways associated with DEmRNAs. We identified the intersection of common DEmRNAs and lncRNAs and constructed a protein-protein interaction (PPI) network. Correlation analysis between the common DEmRNAs and lncRNAs facilitated the construction of a coding-non-coding network. Lastly, serum peripheral blood mononuclear cells (PBMCs) from patients with RA and OP, as well as healthy controls, were obtained for TRAP staining and qRT-PCR to validate the findings obtained from the online dataset assessments. RESULTS A total of 28 DEmRNAs and 2 DElncRNAs were identified in individuals with both RA and OP. Chromosomal distribution analysis of the consensus DEmRNAs revealed that chromosome 1 had the highest number of differential expression genes. GO and KEGG analyses indicated that these DEmRNAs were primarily associated with " platelets (PLTs) degranulation", "platelet alpha granules", "platelet activation", "tight junctions" and "leukocyte transendothelial migration", with many genes functionally related to PLTs. In the PPI network, MT-ATP6 and PTGS1 emerged as potential hub genes, with MT-ATP6 originating from mitochondrial DNA. Co-expression analysis identified two key lncRNA-mRNA pairs: RP11 - 815J21.2 with MT - ATP6 and RP11 - 815J21.2 with PTGS1. Experimental validation confirmed significant differential expression of RP11-815J21.2, MT-ATP6 and PTGS1 between the healthy controls and the RA + OP groups. Notably, knockdown of RP11-815J21.2 attenuated TNF + IL-6-induced osteoclastogenesis. CONCLUSIONS This study successfully identified shared dysregulated genes and potential therapeutic targets in individuals with RA and OP, highlighting their molecular similarities. These findings provide new insights into the pathogenesis of RA and OP and suggest potential avenues for further research and targeted therapies.
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Affiliation(s)
- Jin-Yu An
- Department of Orthopedics, Changzhou Fourth People's Hospital, Changzhou, 213000, China.
| | - Xing-Na Ma
- Department of Pediatric, Changzhou Fourth People's Hospital, Changzhou, 213000, China
| | - Hui-Long Wen
- Department of Orthopedics, Changzhou Fourth People's Hospital, Changzhou, 213000, China
| | - Hui-Dong Hu
- Department of Orthopedics, Changzhou Fourth People's Hospital, Changzhou, 213000, China
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10
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Busse E, Lee B, Nagamani SCS. Genetic Evaluation for Monogenic Disorders of Low Bone Mass and Increased Bone Fragility: What Clinicians Need to Know. Curr Osteoporos Rep 2024; 22:308-317. [PMID: 38600318 DOI: 10.1007/s11914-024-00870-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/23/2024] [Indexed: 04/12/2024]
Abstract
PURPOSE OF REVIEW The purpose of this review is to outline the principles of clinical genetic testing and to provide practical guidance to clinicians in navigating genetic testing for patients with suspected monogenic forms of osteoporosis. RECENT FINDINGS Heritability assessments and genome-wide association studies have clearly shown the significant contributions of genetic variations to the pathogenesis of osteoporosis. Currently, over 50 monogenic disorders that present primarily with low bone mass and increased risk of fractures have been described. The widespread availability of clinical genetic testing offers a valuable opportunity to correctly diagnose individuals with monogenic forms of osteoporosis, thus instituting appropriate surveillance and treatment. Clinical genetic testing may identify the appropriate diagnosis in a subset of patients with low bone mass, multiple or unusual fractures, and severe or early-onset osteoporosis, and thus clinicians should be aware of how to incorporate such testing into their clinical practices.
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Affiliation(s)
- Emily Busse
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA
| | - Brendan Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
- Texas Children's Hospital, Houston, TX, USA.
| | - Sandesh C S Nagamani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
- Texas Children's Hospital, Houston, TX, USA
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11
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Zhang YY, Xie N, Sun XD, Nice EC, Liou YC, Huang C, Zhu H, Shen Z. Insights and implications of sexual dimorphism in osteoporosis. Bone Res 2024; 12:8. [PMID: 38368422 PMCID: PMC10874461 DOI: 10.1038/s41413-023-00306-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 11/04/2023] [Accepted: 11/27/2023] [Indexed: 02/19/2024] Open
Abstract
Osteoporosis, a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture, has led to a high risk of fatal osteoporotic fractures worldwide. Accumulating evidence has revealed that sexual dimorphism is a notable feature of osteoporosis, with sex-specific differences in epidemiology and pathogenesis. Specifically, females are more susceptible than males to osteoporosis, while males are more prone to disability or death from the disease. To date, sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone cells. Understanding the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and men. This literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis, mainly in a population of aging patients, chronic glucocorticoid administration, and diabetes. Moreover, we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and men. Additionally, the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.
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Affiliation(s)
- Yuan-Yuan Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Na Xie
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Xiao-Dong Sun
- West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Yih-Cherng Liou
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Republic of Singapore
| | - Canhua Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China
| | - Huili Zhu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, Department of Reproductive Medicine, West China Second University Hospital of Sichuan University, Chengdu, China.
| | - Zhisen Shen
- Department of Otorhinolaryngology and Head and Neck Surgery, The Affiliated Lihuili Hospital, Ningbo University, 315040, Ningbo, Zhejiang, China.
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12
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Alqualo NO, Campos-Fernandez E, Picolo BU, Ferreira EL, Henriques LM, Lorenti S, Moreira DC, Simião MPS, Oliveira LBT, Alonso-Goulart V. Molecular biomarkers in prostate cancer tumorigenesis and clinical relevance. Crit Rev Oncol Hematol 2024; 194:104232. [PMID: 38101717 DOI: 10.1016/j.critrevonc.2023.104232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/08/2023] [Accepted: 12/09/2023] [Indexed: 12/17/2023] Open
Abstract
Prostate cancer (PCa) is the second most frequent type of cancer in men and assessing circulating tumor cells (CTCs) by liquid biopsy is a promising tool to help in cancer early detection, staging, risk of recurrence evaluation, treatment prediction and monitoring. Blood-based liquid biopsy approaches enable the enrichment, detection and characterization of CTCs by biomarker analysis. Hence, comprehending the molecular markers, their role on each stage of cancer development and progression is essential to provide information that can help in future implementation of these biomarkers in clinical assistance. In this review, we studied the molecular markers most associated with PCa CTCs to better understand their function on tumorigenesis and metastatic cascade, the methodologies utilized to analyze these biomarkers and their clinical significance, in order to summarize the available information to guide researchers in their investigations, new hypothesis formulation and target choice for the development of new diagnostic and treatment tools.
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Affiliation(s)
- Nathalia Oliveira Alqualo
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Esther Campos-Fernandez
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Bianca Uliana Picolo
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Emanuelle Lorrayne Ferreira
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Laila Machado Henriques
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Sabrina Lorenti
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Danilo Caixeta Moreira
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Maria Paula Silva Simião
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Luciana Beatriz Tiago Oliveira
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Vivian Alonso-Goulart
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil.
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13
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Formosa MM, Christou MA, Mäkitie O. Bone fragility and osteoporosis in children and young adults. J Endocrinol Invest 2024; 47:285-298. [PMID: 37668887 PMCID: PMC10859323 DOI: 10.1007/s40618-023-02179-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 09/06/2023]
Abstract
Osteoporosis is a metabolic bone disorder which increases fragility fracture risk. Elderly individuals, especially postmenopausal women, are particularly susceptible to osteoporosis. Although rare, osteoporosis in children and young adults is becoming increasingly evident, highlighting the need for timely diagnosis, management and follow-up. Early-onset osteoporosis is defined as the presence of a low BMD (Z-score of ≤ -2.0 in individuals aged < 20 years; T-score of ≤ -2.5 in those aged between 20 to 50 years) accompanied by a clinically significant fracture history, or the presence of low-energy vertebral compression fractures even in the absence of osteoporosis. Affected children and young adults should undergo a thorough diagnostic workup, including collection of clinical history, radiography, biochemical investigation and possibly bone biopsy. Once secondary factors and comorbidities are excluded, genetic testing should be considered to determine the possibility of an underlying monogenic cause. Defects in genes related to type I collagen biosynthesis are the commonest contributors of primary osteoporosis, followed by loss-of-function variants in genes encoding key regulatory proteins of canonical WNT signalling (specifically LRP5 and WNT1), the actin-binding plastin-3 protein (encoded by PLS3) resulting in X-linked osteoporosis, and the more recent sphingomyelin synthase 2 (encoded by SGMS2) which is critical for signal transduction affecting sphingomyelin metabolism. Despite these discoveries, genetic causes and underlying mechanisms in early-onset osteoporosis remain largely unknown, and if no causal gene is identified, early-onset osteoporosis is deemed idiopathic. This calls for further research to unravel the molecular mechanisms driving early-onset osteoporosis that consequently will aid in patient management and individualised targeted therapy.
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Affiliation(s)
- M M Formosa
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
- Center for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M A Christou
- Department of Endocrinology, School of Medicine, University of Ioannina, Ioannina, Greece
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece
| | - O Mäkitie
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Folkhälsan Research Centre, Folkhälsan Institute of Genetics, Helsinki, Finland.
- Department of Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
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14
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Costa A, Martins A, Machado C, Lundberg E, Nilsson O, Wang F, Costantini A, Tournis S, Höppner J, Grasemann C, Mäkitie O. PLS3 Mutations in X-Linked Osteoporosis: Clinical and Genetic Features in Five New Families. Calcif Tissue Int 2024; 114:157-170. [PMID: 38043102 PMCID: PMC10803541 DOI: 10.1007/s00223-023-01162-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/06/2023] [Indexed: 12/05/2023]
Abstract
Childhood-onset osteoporosis is a rare but clinically significant condition. Studies have shown pathogenic variants in more than 20 different genes as causative for childhood-onset primary osteoporosis. The X-chromosomal PLS3, encoding Plastin-3, is one of the more recently identified genes. In this study, we describe five new families from four different European countries with PLS3-related skeletal fragility. The index cases were all hemizygous males presenting with long bone and vertebral body compression fractures. All patients had low lumbar spine bone mineral density (BMD). The age at the first clinical fracture ranged from 1.5 to 13 years old. Three of the identified PLS3 variants were stop-gain variants and two were deletions involving either a part or all exons of the gene. In four families the variant was inherited from the mother. All heterozygous women reported here had normal BMD and no bone fractures. Four patients received bisphosphonate treatment with good results, showing a lumbar spine BMD increment and vertebral body reshaping after 10 months to 2 years of treatment. Our findings expand the genetic spectrum of PLS3-related osteoporosis. Our report also shows that early treatment with bisphosphonates may influence the disease course and reduce the progression of osteoporosis, highlighting the importance of early diagnosis for prompt intervention and appropriate genetic counseling.
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Affiliation(s)
- Adriana Costa
- Department of Pediatrics, Hospital Prof. Doutor Fernando Fonseca EPE, Amadora, Portugal.
| | - Andreia Martins
- Department of Pediatrics, Hospital Prof. Doutor Fernando Fonseca EPE, Amadora, Portugal
| | - Catarina Machado
- Department of Pediatrics, Hospital Prof. Doutor Fernando Fonseca EPE, Amadora, Portugal
| | - Elena Lundberg
- Department of Pediatrics, Institution of Clinical Science, Umea University, Umeå, Sweden
| | - Ola Nilsson
- Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
- Department of Medical Sciences, Örebro University and University Hospital, Örebro, Sweden
| | - Fan Wang
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Alice Costantini
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Symeon Tournis
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", Medical School, University of Athens, Athens, Greece
| | - Jakob Höppner
- Department of Pediatrics, St. Josef-Hospital Bochum, Ruhr-University Bochum, Bochum, Germany
- Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Corinna Grasemann
- Department of Pediatrics, St. Josef-Hospital Bochum, Ruhr-University Bochum, Bochum, Germany
| | - Outi Mäkitie
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Folkhälsan Research Center, Helsinki, Finland
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15
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Maus I, Dreiner M, Zetzsche S, Metzen F, Ross BC, Mählich D, Koch M, Niehoff A, Wirth B. Osteoclast-specific Plastin 3 knockout in mice fail to develop osteoporosis despite dramatic increased osteoclast resorption activity. JBMR Plus 2024; 8:ziad009. [PMID: 38549711 PMCID: PMC10971598 DOI: 10.1093/jbmrpl/ziad009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/11/2023] [Accepted: 11/26/2023] [Indexed: 05/07/2024] Open
Abstract
PLS3 loss-of-function mutations in humans and mice cause X-linked primary osteoporosis. However, it remains largely unknown how PLS3 mutations cause osteoporosis and which function PLS3 plays in bone homeostasis. A recent study showed that ubiquitous Pls3 KO in mice results in osteoporosis. Mainly osteoclasts were impacted in their function However, it has not been proven if osteoclasts are the major cell type affected and responsible for osteoporosis development in ubiquitous Pls3 KO mice. Here, we generated osteoclast-specific Pls3 KO mice. Additionally, we developed a novel polyclonal PLS3 antibody that showed specific PLS3 loss in immunofluorescence staining of osteoclasts in contrast to previously available antibodies against PLS3, which failed to show PLS3 specificity in mouse cells. Moreover, we demonstrate that osteoclast-specific Pls3 KO causes dramatic increase in resorptive activity of osteoclasts in vitro. Despite these findings, osteoclast-specific Pls3 KO in vivo failed to cause any osteoporotic phenotype in mice as proven by micro-CT and three-point bending test. This demonstrates that the pathomechanism of PLS3-associated osteoporosis is highly complex and cannot be reproduced in a system singularly focused on one cell type. Thus, the loss of PLS3 in alternative bone cell types might contributes to the osteoporosis phenotype in ubiquitous Pls3 KO mice.
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Affiliation(s)
- Ilka Maus
- Institute of Human Genetics, University of Cologne, University Hospital of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
| | - Maren Dreiner
- Institute of Biomechanics and Orthopaedics, German Sport University Cologne, 50933 Cologne, Germany
| | - Sebastian Zetzsche
- Institute of Human Genetics, University of Cologne, University Hospital of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
| | - Fabian Metzen
- Medical Faculty, Institute for Dental Research and Oral Musculoskeletal Biology, University of Cologne, 50931 Cologne, Germany
- Medical Faculty, Center for Biochemistry, University of Cologne, 50931 Cologne, Germany
| | - Bryony C Ross
- Institute of Human Genetics, University of Cologne, University Hospital of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
| | - Daniela Mählich
- Institute of Biomechanics and Orthopaedics, German Sport University Cologne, 50933 Cologne, Germany
| | - Manuel Koch
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
- Medical Faculty, Institute for Dental Research and Oral Musculoskeletal Biology, University of Cologne, 50931 Cologne, Germany
- Medical Faculty, Center for Biochemistry, University of Cologne, 50931 Cologne, Germany
| | - Anja Niehoff
- Institute of Biomechanics and Orthopaedics, German Sport University Cologne, 50933 Cologne, Germany
- Faculty of Medicine, Cologne Center for Musculoskeletal Biomechanics (CCMB), University of Cologne, 50931 Cologne, Germany
| | - Brunhilde Wirth
- Institute of Human Genetics, University of Cologne, University Hospital of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany
- Center for Rare Diseases, University of Cologne, University Hospital of Cologne, 50931 Cologne, Germany
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16
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Chin SM, Unnold-Cofre C, Naismith T, Jansen S. The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization. Front Cell Dev Biol 2023; 11:1141738. [PMID: 38089885 PMCID: PMC10711096 DOI: 10.3389/fcell.2023.1141738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 11/07/2023] [Indexed: 02/01/2024] Open
Abstract
Plastin-3 (PLS3) is a calcium-sensitive actin-bundling protein that has recently been linked to the development of childhood-onset osteoporosis. Clinical data suggest that PLS3 mutations lead to a defect in osteoblast function, however the underlying mechanism remains elusive. To investigate the role of PLS3 in bone mineralization, we generated MC3T3-E1 preosteoblast cells that are stably depleted of PLS3. Analysis of osteogenic differentiation of control and PLS3 knockdown (PLS3 KD) cells showed that depletion of PLS3 does not alter the first stage of osteoblast mineralization in which a collagen matrix is deposited, but severely affects the subsequent mineralization of that matrix. During this phase, osteoblasts heavily rely on mechanosensitive signaling pathways to sustain mineral deposition in response to increasing stiffness of the extracellular matrix (ECM). PLS3 prominently localizes to focal adhesions (FAs), which are intricately linked to mechanosensation. In line with this, we observed that depletion of PLS3 rendered osteoblasts unresponsive to changes in ECM stiffness and showed the same cell size, FA lengths and number of FAs when plated on soft (6 kPa) versus stiff (100 kPa) substrates in contrast to control cells, which showed an increased in each of these parameters when plated on 100 kPa substrates. Defective cell spreading of PLS3 KD cells on stiff substrates could be rescued by expression of wildtype PLS3, but not by expression of three PLS3 mutations that were identified in patients with early onset osteoporosis and that have aberrant actin-bundling activity. Altogether, our results show that actin-bundling by PLS3 is part of the mechanosensitive mechanism that promotes osteoblast mineralization and thus begins to elucidate how PLS3 contributes to the development of bone defects such as osteoporosis.
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Affiliation(s)
| | | | | | - Silvia Jansen
- Department of Cell Biology and Physiology, Washington University in St. Louis, Saint Louis, MO, United States
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17
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Petit F, Longoni M, Wells J, Maser RS, Bogenschutz EL, Dysart MJ, Contreras HTM, Frénois F, Pober BR, Clark RD, Giampietro PF, Ropers HH, Hu H, Loscertales M, Wagner R, Ai X, Brand H, Jourdain AS, Delrue MA, Gilbert-Dussardier B, Devisme L, Keren B, McCulley DJ, Qiao L, Hernan R, Wynn J, Scott TM, Calame DG, Coban-Akdemir Z, Hernandez P, Hernandez-Garcia A, Yonath H, Lupski JR, Shen Y, Chung WK, Scott DA, Bult CJ, Donahoe PK, High FA. PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects. Am J Hum Genet 2023; 110:1787-1803. [PMID: 37751738 PMCID: PMC10577083 DOI: 10.1016/j.ajhg.2023.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 08/31/2023] [Accepted: 09/01/2023] [Indexed: 09/28/2023] Open
Abstract
Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical phenotypes. The missense variants in individuals with CDH are located within the actin-binding domains of the protein but are not predicted to affect protein structure, whereas the variants in individuals with osteoporosis are predicted to result in loss of function. A mouse knockin model of a variant identified in one of the CDH-affected families, c.1497G>C (p.Trp499Cys), shows partial perinatal lethality and recapitulates the key findings of the human phenotype, including diaphragm and abdominal-wall defects. Both the mouse model and one adult human male with a CDH-associated PLS3 variant were observed to have increased rather than decreased bone mineral density. Together, these clinical and functional data in humans and mice reveal that specific missense variants affecting the actin-binding domains of PLS3 might have a gain-of-function effect and cause a Mendelian congenital disorder.
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Affiliation(s)
- Florence Petit
- Clinique de Génétique, CHU de Lille, Lille, France; EA7364 RADEME, Université de Lille, Lille, France
| | - Mauro Longoni
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA
| | | | | | | | - Matthew J Dysart
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA
| | - Hannah T M Contreras
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA
| | | | - Barbara R Pober
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA
| | - Robin D Clark
- Division of Genetics, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | | | - Hilger H Ropers
- Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Hao Hu
- Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Maria Loscertales
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA
| | - Richard Wagner
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA; Department of Pediatric Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Xingbin Ai
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA
| | - Harrison Brand
- Department of Neurology, Harvard Medical School, Boston, MA, USA
| | | | | | | | | | - Boris Keren
- Département de Génétique, Hôpital Pitié Salpétrière, CHU de Paris, Paris, France
| | - David J McCulley
- Department of Pediatrics, University of California, San Diego, San Diego, CA, USA
| | - Lu Qiao
- Department of Pediatrics, Columbia University, New York, NY, USA
| | - Rebecca Hernan
- Department of Pediatrics, Columbia University, New York, NY, USA
| | - Julia Wynn
- Department of Pediatrics, Columbia University, New York, NY, USA
| | - Tiana M Scott
- Department of Microbiology and Molecular Biology, College of Life Sciences, Brigham Young University, Provo, UT, USA
| | - Daniel G Calame
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA
| | - Zeynep Coban-Akdemir
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, the University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Patricia Hernandez
- IDDRC/TCC, Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | | | - Hagith Yonath
- Internal Medicine A and Genetics Institute, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - James R Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Yufeng Shen
- Department of Systems Biology, Columbia University, New York, NY, USA
| | - Wendy K Chung
- Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA
| | - Daryl A Scott
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA
| | | | - Patricia K Donahoe
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA
| | - Frances A High
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA; Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Boston Children's Hospital, Boston, MA, USA.
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18
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Zhong W, Pathak JL, Liang Y, Zhytnik L, Pals G, Eekhoff EMW, Bravenboer N, Micha D. The intricate mechanism of PLS3 in bone homeostasis and disease. Front Endocrinol (Lausanne) 2023; 14:1168306. [PMID: 37484945 PMCID: PMC10361617 DOI: 10.3389/fendo.2023.1168306] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/19/2023] [Indexed: 07/25/2023] Open
Abstract
Since our discovery in 2013 that genetic defects in PLS3 lead to bone fragility, the mechanistic details of this process have remained obscure. It has been established that PLS3 variants cause syndromic and nonsyndromic osteoporosis as well as osteoarthritis. PLS3 codes for an actin-bundling protein with a broad pattern of expression. As such, it is puzzling how PLS3 specifically leads to bone-related disease presentation. Our review aims to summarize the current state of knowledge regarding the function of PLS3 in the predominant cell types in the bone tissue, the osteocytes, osteoblasts and osteoclasts. This is related to the role of PLS3 in regulating mechanotransduction, calcium regulation, vesicle trafficking, cell differentiation and mineralization as part of the complex bone pathology presented by PLS3 defects. Considering the consequences of PLS3 defects on multiple aspects of bone tissue metabolism, our review motivates the study of its mechanism in bone diseases which can potentially help in the design of suitable therapy.
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Affiliation(s)
- Wenchao Zhong
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Department of Clinical Chemistry, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Amsterdam Movement Sciences, Tissue Function And Regeneration, Amsterdam, Netherlands
- Department of Temporomandibular Joint, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Janak L. Pathak
- Department of Temporomandibular Joint, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yueting Liang
- Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, China
- The Second Clinical College, Guangzhou Medical University, Guangzhou, China
| | - Lidiia Zhytnik
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Amsterdam Movement Sciences, Tissue Function And Regeneration, Amsterdam, Netherlands
- Department of Traumatology and Orthopaedics, Institute of Clinical Medicine, The University of Tartu, Tartu, Estonia
| | - Gerard Pals
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Amsterdam Movement Sciences, Tissue Function And Regeneration, Amsterdam, Netherlands
| | - Elisabeth M. W. Eekhoff
- Department Internal Medicine Section Endocrinology and Metabolism, Amsterdam UMC Location Vrije Universiteit Amsterdam, Rare Bone Disease Center, AMS, Amsterdam, Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, Netherlands
| | - Nathalie Bravenboer
- Department of Clinical Chemistry, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Amsterdam Movement Sciences, Tissue Function And Regeneration, Amsterdam, Netherlands
| | - Dimitra Micha
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Amsterdam Movement Sciences, Tissue Function And Regeneration, Amsterdam, Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam, Netherlands
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19
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Verdonk SJE, Storoni S, Zhytnik L, Zhong W, Pals G, van Royen BJ, Elting MW, Maugeri A, Eekhoff EMW, Micha D. Medical Care Use Among Patients with Monogenic Osteoporosis Due to Rare Variants in LRP5, PLS3, or WNT1. Calcif Tissue Int 2023:10.1007/s00223-023-01101-3. [PMID: 37277619 PMCID: PMC10371905 DOI: 10.1007/s00223-023-01101-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 05/19/2023] [Indexed: 06/07/2023]
Abstract
Pathogenic variants in the LRP5, PLS3, or WNT1 genes can significantly affect bone mineral density, causing monogenic osteoporosis. Much remains to be discovered about the phenotype and medical care needs of these patients. The purpose of this study was to examine the use of medical care among Dutch individuals identified between 2014 and 2021 with a pathogenic or suspicious rare variant in LRP5, PLS3, or WNT1. In addition, the aim was to compare their medical care utilization to both the overall Dutch population and the Dutch Osteogenesis Imperfecta (OI) population. The Amsterdam UMC Genome Database was used to match 92 patients with the Statistics Netherlands (CBS) cohort. Patients were categorized based on their harbored variants: LRP5, PLS3, or WNT1. Hospital admissions, outpatient visits, medication data, and diagnosis treatment combinations (DTCs) were compared between the variant groups and, when possible, to the total population and OI population. Compared to the total population, patients with an LRP5, PLS3, or WNT1 variant had 1.63 times more hospital admissions, 2.0 times more opened DTCs, and a greater proportion using medication. Compared to OI patients, they had 0.62 times fewer admissions. Dutch patients with an LRP5, PLS3, or WNT1 variant appear to require on average more medical care than the total population. As expected, they made higher use of care at the surgical and orthopedic departments. Additionally, they used more care at the audiological centers and the otorhinolaryngology (ENT) department, suggesting a higher risk of hearing-related problems.
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Affiliation(s)
- S J E Verdonk
- Department of Internal Medicine Section Endocrinology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
- Rare Bone Disease Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam Movement Sciences, Tissue Function and Regeneration, Amsterdam, The Netherlands
| | - S Storoni
- Department of Internal Medicine Section Endocrinology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
- Rare Bone Disease Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam Movement Sciences, Tissue Function and Regeneration, Amsterdam, The Netherlands
| | - L Zhytnik
- Rare Bone Disease Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam Movement Sciences, Tissue Function and Regeneration, Amsterdam, The Netherlands
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
- Department of Traumatology and Orthopedics, University of Tartu, Tartu, Estonia
| | - W Zhong
- Rare Bone Disease Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam Movement Sciences, Tissue Function and Regeneration, Amsterdam, The Netherlands
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
| | - G Pals
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
| | - B J van Royen
- Department of Orthopedic Surgery and Sports Medicine, Amsterdam UMC Location University of Amsterdam and Location Vrije Universiteit Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands
- Amsterdam Movement Sciences, Musculoskeletal Health, Amsterdam, The Netherlands
| | - M W Elting
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
| | - A Maugeri
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
| | - E M W Eekhoff
- Department of Internal Medicine Section Endocrinology, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
- Rare Bone Disease Center Amsterdam, Amsterdam, The Netherlands.
- Amsterdam Movement Sciences, Tissue Function and Regeneration, Amsterdam, The Netherlands.
| | - D Micha
- Rare Bone Disease Center Amsterdam, Amsterdam, The Netherlands
- Amsterdam Movement Sciences, Tissue Function and Regeneration, Amsterdam, The Netherlands
- Department of Human Genetics, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands
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20
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Strathmann EA, Hölker I, Tschernoster N, Hosseinibarkooie S, Come J, Martinat C, Altmüller J, Wirth B. Epigenetic regulation of plastin 3 expression by the macrosatellite DXZ4 and the transcriptional regulator CHD4. Am J Hum Genet 2023; 110:442-459. [PMID: 36812914 PMCID: PMC10027515 DOI: 10.1016/j.ajhg.2023.02.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 02/03/2023] [Indexed: 02/23/2023] Open
Abstract
Dysregulated Plastin 3 (PLS3) levels associate with a wide range of skeletal and neuromuscular disorders and the most common types of solid and hematopoietic cancer. Most importantly, PLS3 overexpression protects against spinal muscular atrophy. Despite its crucial role in F-actin dynamics in healthy cells and its involvement in many diseases, the mechanisms that regulate PLS3 expression are unknown. Interestingly, PLS3 is an X-linked gene and all asymptomatic SMN1-deleted individuals in SMA-discordant families who exhibit PLS3 upregulation are female, suggesting that PLS3 may escape X chromosome inactivation. To elucidate mechanisms contributing to PLS3 regulation, we performed a multi-omics analysis in two SMA-discordant families using lymphoblastoid cell lines and iPSC-derived spinal motor neurons originated from fibroblasts. We show that PLS3 tissue-specifically escapes X-inactivation. PLS3 is located ∼500 kb proximal to the DXZ4 macrosatellite, which is essential for X chromosome inactivation. By applying molecular combing in a total of 25 lymphoblastoid cell lines (asymptomatic individuals, individuals with SMA, control subjects) with variable PLS3 expression, we found a significant correlation between the copy number of DXZ4 monomers and PLS3 levels. Additionally, we identified chromodomain helicase DNA binding protein 4 (CHD4) as an epigenetic transcriptional regulator of PLS3 and validated co-regulation of the two genes by siRNA-mediated knock-down and overexpression of CHD4. We show that CHD4 binds the PLS3 promoter by performing chromatin immunoprecipitation and that CHD4/NuRD activates the transcription of PLS3 by dual-luciferase promoter assays. Thus, we provide evidence for a multilevel epigenetic regulation of PLS3 that may help to understand the protective or disease-associated PLS3 dysregulation.
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Affiliation(s)
- Eike A Strathmann
- Institute of Human Genetics, University Hospital of Cologne, University Cologne, Kerpener Str. 34, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany
| | - Irmgard Hölker
- Institute of Human Genetics, University Hospital of Cologne, University Cologne, Kerpener Str. 34, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany
| | - Nikolai Tschernoster
- Institute of Human Genetics, University Hospital of Cologne, University Cologne, Kerpener Str. 34, 50931 Cologne, Germany; Cologne Center for Genomics and West German Genome Center, University of Cologne, 50931 Cologne, Germany
| | - Seyyedmohsen Hosseinibarkooie
- Institute of Human Genetics, University Hospital of Cologne, University Cologne, Kerpener Str. 34, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany
| | - Julien Come
- INSERM/ UEVE UMR 861, Université Paris Saclay, I-STEM, 91100 Corbeil-Essonnes, France
| | - Cecile Martinat
- INSERM/ UEVE UMR 861, Université Paris Saclay, I-STEM, 91100 Corbeil-Essonnes, France
| | - Janine Altmüller
- Cologne Center for Genomics and West German Genome Center, University of Cologne, 50931 Cologne, Germany
| | - Brunhilde Wirth
- Institute of Human Genetics, University Hospital of Cologne, University Cologne, Kerpener Str. 34, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Center for Rare Diseases, University Hospital of Cologne, 50931 Cologne, Germany.
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21
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PLS3 whole gene deletion as a cause of X-linked osteoporosis: Clinical report with review of published PLS3 literature. Clin Dysmorphol 2023; 32:43-47. [PMID: 36503925 DOI: 10.1097/mcd.0000000000000442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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22
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Lv F, Cai X, Ji L. An Update on Animal Models of Osteogenesis Imperfecta. Calcif Tissue Int 2022; 111:345-366. [PMID: 35767009 DOI: 10.1007/s00223-022-00998-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 06/01/2022] [Indexed: 11/02/2022]
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous disorder characterized by bone fragility, multiple fractures, bone deformity, and short stature. In recent years, the application of next generation sequencing has triggered the discovery of many new genetic causes for OI. Until now, more than 25 genetic causes of OI and closely related disorders have been identified. However, the mechanisms of many genes on skeletal fragility in OI are not entirely clear. Animal models of OI could help to understand the cellular, signaling, and metabolic mechanisms contributing to the disease, and how targeting these pathways can provide therapeutic targets. To date, a lot of animal models, mainly mice and zebrafish, have been described with defects in 19 OI-associated genes. In this review, we summarize the known genetic causes and animal models that recapitulate OI with a main focus on engineered mouse and zebrafish models. Additionally, we briefly discuss domestic animals with naturally occurring OI phenotypes. Knowledge of the specific molecular basis of OI will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches.
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Affiliation(s)
- Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Xizhimen South Street No.11, Beijing, 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Xizhimen South Street No.11, Beijing, 100044, China.
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Xizhimen South Street No.11, Beijing, 100044, China.
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23
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Costantini A, Mäkitie RE, Hartmann MA, Fratzl-Zelman N, Zillikens MC, Kornak U, Søe K, Mäkitie O. Early-Onset Osteoporosis: Rare Monogenic Forms Elucidate the Complexity of Disease Pathogenesis Beyond Type I Collagen. J Bone Miner Res 2022; 37:1623-1641. [PMID: 35949115 PMCID: PMC9542053 DOI: 10.1002/jbmr.4668] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 07/22/2022] [Accepted: 08/01/2022] [Indexed: 12/05/2022]
Abstract
Early-onset osteoporosis (EOOP), characterized by low bone mineral density (BMD) and fractures, affects children, premenopausal women and men aged <50 years. EOOP may be secondary to a chronic illness, long-term medication, nutritional deficiencies, etc. If no such cause is identified, EOOP is regarded primary and may then be related to rare variants in genes playing a pivotal role in bone homeostasis. If the cause remains unknown, EOOP is considered idiopathic. The scope of this review is to guide through clinical and genetic diagnostics of EOOP, summarize the present knowledge on rare monogenic forms of EOOP, and describe how analysis of bone biopsy samples can lead to a better understanding of the disease pathogenesis. The diagnostic pathway of EOOP is often complicated and extensive assessments may be needed to reliably exclude secondary causes. Due to the genetic heterogeneity and overlapping features in the various genetic forms of EOOP and other bone fragility disorders, the genetic diagnosis usually requires the use of next-generation sequencing to investigate several genes simultaneously. Recent discoveries have elucidated the complexity of disease pathogenesis both regarding genetic architecture and bone tissue-level pathology. Two rare monogenic forms of EOOP are due to defects in genes partaking in the canonical WNT pathway: LRP5 and WNT1. Variants in the genes encoding plastin-3 (PLS3) and sphingomyelin synthase 2 (SGMS2) have also been found in children and young adults with skeletal fragility. The molecular mechanisms leading from gene defects to clinical manifestations are often not fully understood. Detailed analysis of patient-derived transiliac bone biopsies gives valuable information to understand disease pathogenesis, distinguishes EOOP from other bone fragility disorders, and guides in patient management, but is not widely available in clinical settings. Despite the great advances in this field, EOOP remains an insufficiently explored entity and further research is needed to optimize diagnostic and therapeutic approaches. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Alice Costantini
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Paris Cité University, INSERM UMR1163, Institut Imagine, Paris, France
| | - Riikka E Mäkitie
- Folkhälsan Institute of Genetics, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Markus A Hartmann
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria.,Vienna Bone and Growth Center, Vienna, Austria
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria.,Vienna Bone and Growth Center, Vienna, Austria
| | - M Carola Zillikens
- Bone Center, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Uwe Kornak
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Kent Søe
- Clinical Cell Biology, Department of Pathology, Odense University Hospital, Odense, Denmark.,Clinical Cell Biology, Pathology Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Outi Mäkitie
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Folkhälsan Institute of Genetics, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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24
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Qiu C, Li QW, Zhang L, Liu XL. X-linked osteogenesis imperfecta accompanied by patent ductus arteriosus: a case with a novel splice variant in PLS3. World J Pediatr 2022; 18:515-519. [PMID: 35349104 DOI: 10.1007/s12519-022-00539-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/02/2022] [Indexed: 11/26/2022]
Affiliation(s)
- Chuang Qiu
- Department of Orthopaedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qi-Wei Li
- Department of Pediatric Orthopaedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lu Zhang
- Department of Clinical Genetics, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China
| | - Xiao-Liang Liu
- Department of Clinical Genetics, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China.
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25
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Wu Z, Feng Z, Zhu X, Dai Z, Min K, Qiu Y, Yi L, Xu L, Zhu Z. Identification of a novel splicing mutation and genotype-phenotype correlations in rare PLS3-related childhood-onset osteoporosis. Orphanet J Rare Dis 2022; 17:247. [PMID: 35752817 PMCID: PMC9233774 DOI: 10.1186/s13023-022-02380-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 06/06/2022] [Indexed: 11/16/2022] Open
Abstract
Background X-linked early-onset osteoporosis, caused by mutations in plastin3 (PLS3), is an extremely rare disease characterized by low bone mineral density (BMD) and recurrent osteoporotic fractures. There is limited information on genetic and phenotypic spectrum, as well as genotype–phenotype correlations of the disease. Moreover, whether decreased PLS3 levels were also involved in osteoporosis among subjects without PLS3 pathogenic mutations remains unknown. Methods Whole-exome sequencing and bidirectional Sanger sequencing were performed for screening and validation of pathogenic mutations. Serum biochemical parameters and clinical information of the subjects were retrospectively collected. ELISA and online datasets were utilized to investigate the association between PLS3 expression and BMD. Results We identified a novel splicing mutation (c.892-2A > G) which led to the skipping of exon 9 in a family with X-linked early-onset osteoporosis. Scoliosis represents a potential new phenotype in the patients harboring PLS3 mutations, which may be corrected by brace treatment. Genotype–phenotype analysis reveals that there was no significant difference in BMD z-scores between different types of reported mutations including this study (p = 0.5). There is a marginally significant negative correlation between age and BMD z-score (p = 0.059, r = − 0.30). The conditions of osteoporosis in all patients were improved after bisphosphonates therapy, with mean BMD z-score increased from − 2.9 to − 0.57 (p < 0.0001). Serum PLS3 levels in adolescents and adults without PLS3 pathogenic mutations but representing osteoporosis were also evaluated, while no association was found between bone mineral density and PLS3 levels (p > 0.05). Conclusions Our findings expanded the mutation and phenotype spectrum of the rare disease and highlights the importance of early diagnosis and early treatment with bisphosphonates. More reports of cases with PLS3 mutation and function studies of the gene are warranted to understand genotype–phenotype correlations. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02380-z.
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Affiliation(s)
- Zhichong Wu
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Zhenhua Feng
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Xiufen Zhu
- Osteoporosis and Metabolic Bone Disease Center, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhicheng Dai
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Kaixing Min
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Yong Qiu
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Long Yi
- Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing, China
| | - Leilei Xu
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Zezhang Zhu
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. .,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China.
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26
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Abstract
Osteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < - 2.0 in growing children and a Z-score ≤ - 2.0 or a T-score ≤ - 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in LRP5 and WNT1 may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by PLS3 gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to SGMS2 mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.
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Affiliation(s)
- Outi Mäkitie
- Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Folkhälsan Research Center, Biomedicum Helsinki, P.O. Box 63, FI-00014, Helsinki, Finland.
| | - M Carola Zillikens
- Department of Internal Medicine, Erasmus University Medical Center, 3015, Rotterdam, The Netherlands
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27
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Vilaca T, Eastell R, Schini M. Osteoporosis in men. Lancet Diabetes Endocrinol 2022; 10:273-283. [PMID: 35247315 DOI: 10.1016/s2213-8587(22)00012-2] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/06/2022] [Accepted: 01/07/2022] [Indexed: 12/18/2022]
Abstract
Osteoporosis in men is a common but often overlooked disorder by clinicians. The criterion for osteoporosis diagnosis in men is similar to that in women-namely, a bone mineral density (BMD) that is 2·5 standard deviations or more below the mean for the young adult population (aged 20-29 years; T-score -2·5 or lower), measured at the hip or lumbar spine. Sex steroids are important for bone health in men and, as in women, oestrogens have a key role. Most men generally have bigger and stronger bones than women and typically have less bone loss during their lifetime. Men typically fracture less often than women, although they have a higher mortality rate after a fracture. Secondary osteoporosis is more common in men than in women. Lifestyle changes, adequate calcium, vitamin D intake, and exercise programmes are recommended for the management of osteoporosis in men. Bisphosphonates, denosumab, and teriparatide have been shown to increase BMD and are used for pharmacological treatment. In this Review, we report an updated overview of osteoporosis in men, describe new treatments and concepts, and discuss persistent controversies in the area.
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Affiliation(s)
- Tatiane Vilaca
- Department of Oncology and Metabolism, Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, UK.
| | - Richard Eastell
- Department of Oncology and Metabolism, Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, UK
| | - Marian Schini
- Department of Oncology and Metabolism, Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, UK
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28
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Kague E, Karasik D. Functional Validation of Osteoporosis Genetic Findings Using Small Fish Models. Genes (Basel) 2022; 13:279. [PMID: 35205324 PMCID: PMC8872034 DOI: 10.3390/genes13020279] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/26/2022] [Accepted: 01/27/2022] [Indexed: 12/11/2022] Open
Abstract
The advancement of human genomics has revolutionized our understanding of the genetic architecture of many skeletal diseases, including osteoporosis. However, interpreting results from human association studies remains a challenge, since index variants often reside in non-coding regions of the genome and do not possess an obvious regulatory function. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary, such as the one offered by animal models. These models enable us to identify causal mechanisms, clarify the underlying biology, and apply interventions. Over the past several decades, small teleost fishes, mostly zebrafish and medaka, have emerged as powerful systems for modeling the genetics of human diseases. Due to their amenability to genetic intervention and the highly conserved genetic and physiological features, fish have become indispensable for skeletal genomic studies. The goal of this review is to summarize the evidence supporting the utility of Zebrafish (Danio rerio) for accelerating our understanding of human skeletal genomics and outlining the remaining gaps in knowledge. We provide an overview of zebrafish skeletal morphophysiology and gene homology, shedding light on the advantages of human skeletal genomic exploration and validation. Knowledge of the biology underlying osteoporosis through animal models will lead to the translation into new, better and more effective therapeutic approaches.
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Affiliation(s)
- Erika Kague
- School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK;
| | - David Karasik
- The Musculoskeletal Genetics Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel
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Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta. Genes (Basel) 2022; 13:genes13020204. [PMID: 35205249 PMCID: PMC8871631 DOI: 10.3390/genes13020204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 11/19/2022] Open
Abstract
Background: Osteoporosis is a skeletal disease with a strong genetic background. The study aimed to identify the genetic determinants of early-onset familial osteoporosis and low bone mineral density (BMD) in a two-generation Maltese family. Methods: Fifteen relatives aged between 28–74 years were recruited. Whole genome sequencing was conducted on 12 relatives and shortlisted variants were genotyped in the Malta Osteoporotic Fracture Study (MOFS) for replication. Results: Sequential variant filtering following a dominant inheritance pattern identified rare missense variants within SELP, TGF-β2 and ADAMTS20, all of which were predicted to be likely pathogenic and participate in osteoimmunology. TGF-β2 c.1136C>T was identified in five individuals from the MOFS in heterozygosity, four of whom had osteopenia/osteoporosis at the lumbar spine and hip, and/or had sustained a low-trauma fracture. Heterozygosity for the ADAMTS20 c.4090A>T was accompanied by lower total hip BMD (p = 0.018) and lower total serum calcium levels in MOFS (p < 0.01), recapitulating the findings from the family. Women carrying at least one copy of the alternative allele (TC/CC) for SELP c.2177T>C exhibited a tendency for lower lumbar spine BMD and/or wrist fracture history relative to women with TT genotype. Conclusions: Our findings suggest that the identified variants, alone or in combination, could be causal factors of familial osteoporosis and low BMD, requiring replication in larger collections.
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30
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Cohen A, Hostyk J, Baugh EH, Buchovecky CM, Aggarwal VS, Recker RR, Lappe JM, Dempster DW, Zhou H, Kamanda-Kosseh M, Bucovsky M, Stubby J, Goldstein DB, Shane E. Whole exome sequencing reveals potentially pathogenic variants in a small subset of premenopausal women with idiopathic osteoporosis. Bone 2022; 154:116253. [PMID: 34743040 PMCID: PMC8671293 DOI: 10.1016/j.bone.2021.116253] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 10/30/2021] [Accepted: 11/01/2021] [Indexed: 01/03/2023]
Abstract
Osteoporosis in premenopausal women with intact gonadal function and no known secondary cause of bone loss is termed idiopathic osteoporosis (IOP). Women with IOP diagnosed in adulthood have profound bone structural deficits and often report adult and childhood fractures, and family history of osteoporosis. Some have very low bone formation rates (BFR/BS) suggesting osteoblast dysfunction. These features led us to investigate potential genetic etiologies of bone fragility. In 75 IOP women (aged 20-49) with low trauma fractures and/or very low BMD who had undergone transiliac bone biopsies, we performed Whole Exome Sequencing (WES) using our variant analysis pipeline to select candidate rare and novel variants likely to affect known disease genes. We ran rare-variant burden analyses on all genes individually and on phenotypically-relevant gene sets. For particular genes implicated in osteoporosis, we also assessed the frequency of all (including common) variants in subjects versus 6540 non-comorbid female controls. The variant analysis pipeline identified 4 women with 4 heterozygous variants in LRP5 and PLS3 that were considered to contribute to osteoporosis. All 4 women had adult fractures, and 3 women also had multiple fractures, childhood fractures and a family history of osteoporosis. Two women presented during pregnancy/lactation. In an additional 4 subjects, 4 different relevant Variants of Uncertain Significance (VUS) were detected in the genes FKBP10, SLC34A3, and HGD. Of the subjects with VUS, 2 had multiple adult fractures, childhood fractures, and presented during pregnancy/lactation, and 2 had nephrolithiasis. BFR/BS varied among the 8 subjects with identified variants; BFR/BS was quite low in those with variants that are likely to have adverse effects on bone formation. The analysis pipeline did not discover candidate variants in COL1A1, COL1A2, WNT, or ALPL. Although we found several novel and rare variants in LRP5, cases did not have an increased burden of common LRP5 variants compared to controls. Cohort-wide collapsing analysis did not reveal any novel disease genes with genome-wide significance for qualifying variants between controls and our 75 cases. In summary, WES revealed likely pathogenic variants or relevant VUS in 8 (11%) of 75 women with IOP. Notably, the genetic variants identified were consistent with the affected women's diagnostic evaluations that revealed histological evidence of low BFR/BS or biochemical evidence of increased bone resorption and urinary calcium excretion. These results, and the fact that the majority of the women had no identifiable genetic etiology, also suggest that the pathogenesis of and mechanisms leading to osteoporosis in this cohort are heterogeneous. Future research is necessary to identify both new genetic and non-genetic etiologies of early-onset osteoporosis.
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Affiliation(s)
- Adi Cohen
- Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA.
| | - Joseph Hostyk
- Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Evan H Baugh
- Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Christie M Buchovecky
- Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Vimla S Aggarwal
- Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Robert R Recker
- Department of Medicine, Creighton University Medical Center, Omaha, NE, USA
| | - Joan M Lappe
- Department of Medicine, Creighton University Medical Center, Omaha, NE, USA
| | - David W Dempster
- Department of Pathology and Cell Biology, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
| | - Hua Zhou
- Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York, NY, USA
| | - Mafo Kamanda-Kosseh
- Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
| | - Mariana Bucovsky
- Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
| | - Julie Stubby
- Department of Medicine, Creighton University Medical Center, Omaha, NE, USA
| | - David B Goldstein
- Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Elizabeth Shane
- Department of Medicine, Columbia University Vagelos College of Physicians & Surgeons, New York, NY, USA
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31
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Rauner M, Foessl I, Formosa MM, Kague E, Prijatelj V, Lopez NA, Banerjee B, Bergen D, Busse B, Calado Â, Douni E, Gabet Y, Giralt NG, Grinberg D, Lovsin NM, Solan XN, Ostanek B, Pavlos NJ, Rivadeneira F, Soldatovic I, van de Peppel J, van der Eerden B, van Hul W, Balcells S, Marc J, Reppe S, Søe K, Karasik D. Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques. Front Endocrinol (Lausanne) 2021; 12:731217. [PMID: 34938269 PMCID: PMC8686830 DOI: 10.3389/fendo.2021.731217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 09/30/2021] [Indexed: 12/26/2022] Open
Abstract
The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits ("endophenotypes"), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets.
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Affiliation(s)
- Martina Rauner
- Department of Medicine III, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- University Hospital Carl Gustav Carus, Dresden, Germany
| | - Ines Foessl
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Endocrine Lab Platform, Medical University of Graz, Graz, Austria
| | - Melissa M. Formosa
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
- Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
| | - Erika Kague
- School of Physiology, Pharmacology, and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom
| | - Vid Prijatelj
- Department of Oral and Maxillofacial Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
- The Generation R Study, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Nerea Alonso Lopez
- Rheumatology and Bone Disease Unit, CGEM, Institute of Genetics and Cancer (IGC), Edinburgh, United Kingdom
| | - Bodhisattwa Banerjee
- Musculoskeletal Genetics Laboratory, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Dylan Bergen
- School of Physiology, Pharmacology, and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom
- Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, United Kingdom
| | - Björn Busse
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ângelo Calado
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Centro Académico de Medicina de Lisboa, Lisbon, Portugal
| | - Eleni Douni
- Department of Biotechnology, Agricultural University of Athens, Athens, Greece
- Institute for Bioinnovation, B.S.R.C. “Alexander Fleming”, Vari, Greece
| | - Yankel Gabet
- Department of Anatomy & Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Natalia García Giralt
- Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, Barcelona, Spain
| | - Daniel Grinberg
- Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, CIBERER, IBUB, IRSJD, Barcelona, Spain
| | - Nika M. Lovsin
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Xavier Nogues Solan
- Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, Barcelona, Spain
| | - Barbara Ostanek
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Nathan J. Pavlos
- Bone Biology & Disease Laboratory, School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia
| | | | - Ivan Soldatovic
- Institute of Medical Statistics and Informatic, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Jeroen van de Peppel
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Bram van der Eerden
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Wim van Hul
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
| | - Susanna Balcells
- Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, CIBERER, IBUB, IRSJD, Barcelona, Spain
| | - Janja Marc
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Sjur Reppe
- Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway
- Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Oslo, Norway
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Kent Søe
- Clinical Cell Biology, Department of Pathology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - David Karasik
- Azrieli Faculty of Medicine, Bar-Ilan University, Ramat Gan, Israel
- Marcus Research Institute, Hebrew SeniorLife, Boston, MA, United States
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X-Linked Osteogenesis Imperfecta Possibly Caused by a Novel Variant in PLS3. Genes (Basel) 2021; 12:genes12121851. [PMID: 34946798 PMCID: PMC8701009 DOI: 10.3390/genes12121851] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 12/11/2022] Open
Abstract
Osteogenesis imperfecta (OI) represents a complex spectrum of genetic bone diseases that occur primarily due to mutations and deletions of the COL1A1 and COL1A2 genes. Recent molecular studies of the network of signaling pathways have contributed to a better understanding of bone remodeling and the pathogenesis of OI caused by mutations in many other genes associated with normal bone mineralization. In this paper, a case of a rare X-linked variant of OI with a change in the gene encoding plastin 3—a protein important for the regulation of the actin cytoskeleton, is presented. A 16-year-old patient developed ten bone fractures caused by minor trauma or injury, including a compression fracture of the second lumbar vertebra during his lifetime. Next-generation sequencing analysis did not show pathologically relevant deviations in the COL1A1 and COL1A2 genes. Targeted gene analyses (Skeletal disorder panel) of the patient, his father, mother and sister were then performed, detecting variants of uncertain significance (VUS) for genes PLS3, FN1 and COL11A2. A variant in the PLS3 gene were identified in the patient, his mother and sister. Since the PLS3 gene is located on the X chromosome, the mother and sister showed no signs of the disease. Although the variant in the PLS3 gene (c.685G>A (p.Gly229Arg)) has not yet been described in the literature, nor is its pathogenicity known, clinical findings combined with genetic testing showed that this variant may explain the cause of X-linked OI in our patient. This rare case of the PLS3 variant of X-linked OI might point to a novel target for personalized therapy in patients with this severe disease.
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33
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Vollersen N, Zhao W, Rolvien T, Lange F, Schmidt FN, Sonntag S, Shmerling D, von Kroge S, Stockhausen KE, Sharaf A, Schweizer M, Karsak M, Busse B, Bockamp E, Semler O, Amling M, Oheim R, Schinke T, Yorgan TA. The WNT1 G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV. Bone Res 2021; 9:48. [PMID: 34759273 PMCID: PMC8580994 DOI: 10.1038/s41413-021-00170-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 05/28/2021] [Accepted: 06/27/2021] [Indexed: 12/27/2022] Open
Abstract
The recent identification of homozygous WNT1 mutations in individuals with osteogenesis imperfecta type XV (OI-XV) has suggested that WNT1 is a key ligand promoting the differentiation and function of bone-forming osteoblasts. Although such an influence was supported by subsequent studies, a mouse model of OI-XV remained to be established. Therefore, we introduced a previously identified disease-causing mutation (G177C) into the murine Wnt1 gene. Homozygous Wnt1G177C/G177C mice were viable and did not display defects in brain development, but the majority of 24-week-old Wnt1G177C/G177C mice had skeletal fractures. This increased bone fragility was not fully explained by reduced bone mass but also by impaired bone matrix quality. Importantly, the homozygous presence of the G177C mutation did not interfere with the osteoanabolic influence of either parathyroid hormone injection or activating mutation of LRP5, the latter mimicking the effect of sclerostin neutralization. Finally, transcriptomic analyses revealed that short-term administration of WNT1 to osteogenic cells induced not only the expression of canonical WNT signaling targets but also the expression of genes encoding extracellular matrix modifiers. Taken together, our data demonstrate that regulating bone matrix quality is a primary function of WNT1. They further suggest that individuals with WNT1 mutations should profit from existing osteoanabolic therapies.
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Affiliation(s)
- Nele Vollersen
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Wenbo Zhao
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Tim Rolvien
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Fabiola Lange
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Felix Nikolai Schmidt
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Stephan Sonntag
- PolyGene AG, 8153, Rümlang, Switzerland.,ETH Phenomics Center (EPIC), ETH Zürich, 8092, Zürich, Switzerland
| | | | - Simon von Kroge
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Kilian Elia Stockhausen
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Ahmed Sharaf
- Neuronal and Cellular Signal Transduction, Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Michaela Schweizer
- Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center, Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Meliha Karsak
- Neuronal and Cellular Signal Transduction, Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Björn Busse
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Ernesto Bockamp
- Institute for Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, D 55131, Mainz, Germany
| | - Oliver Semler
- Faculty of Medicine and University Hospital Cologne, Department of Pediatrics, University of Cologne, 50937, Cologne, Germany
| | - Michael Amling
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Ralf Oheim
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Thorsten Schinke
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
| | - Timur Alexander Yorgan
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
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34
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Ghatan S, Costantini A, Li R, De Bruin C, Appelman-Dijkstra NM, Winter EM, Oei L, Medina-Gomez C. The Polygenic and Monogenic Basis of Paediatric Fractures. Curr Osteoporos Rep 2021; 19:481-493. [PMID: 33945105 PMCID: PMC8551106 DOI: 10.1007/s11914-021-00680-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2021] [Indexed: 01/19/2023]
Abstract
PURPOSE OF REVIEW Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped by the individual genetic background influencing the acquisition of bone mineral density, and therefore, the skeletal fragility as shown in adults. Here, we examine paediatric fractures from the perspective of monogenic and complex trait genetics. RECENT FINDINGS Large-scale genome-wide studies in children have identified ~44 genetic loci associated with fracture or bone traits whereas ~35 monogenic diseases characterized by paediatric fractures have been described. Genetic variation can predispose to paediatric fractures through monogenic risk variants with a large effect and polygenic risk involving many variants of small effects. Studying genetic factors influencing peak bone attainment might help in identifying individuals at higher risk of developing early-onset osteoporosis and discovering drug targets to be used as bone restorative pharmacotherapies to prevent, or even reverse, bone loss later in life.
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Affiliation(s)
- S Ghatan
- Translational Skeletal Genomics Group, Department of Internal Medicine, Erasmus MC University Medical Centre, Doctor Molewaterplein 40, Ee-571, 3015, GD, Rotterdam, The Netherlands
- Department of Epidemiology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
| | - A Costantini
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - R Li
- Translational Skeletal Genomics Group, Department of Internal Medicine, Erasmus MC University Medical Centre, Doctor Molewaterplein 40, Ee-571, 3015, GD, Rotterdam, The Netherlands
- Department of Epidemiology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
| | - C De Bruin
- Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands
| | - N M Appelman-Dijkstra
- Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands
| | - E M Winter
- Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands
| | - L Oei
- Translational Skeletal Genomics Group, Department of Internal Medicine, Erasmus MC University Medical Centre, Doctor Molewaterplein 40, Ee-571, 3015, GD, Rotterdam, The Netherlands
- Department of Epidemiology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands
- Department of Internal Medicine, Leiden University Medical Centre, Leiden, The Netherlands
| | - Carolina Medina-Gomez
- Translational Skeletal Genomics Group, Department of Internal Medicine, Erasmus MC University Medical Centre, Doctor Molewaterplein 40, Ee-571, 3015, GD, Rotterdam, The Netherlands.
- Department of Epidemiology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands.
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35
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Marí-Beffa M, Mesa-Román AB, Duran I. Zebrafish Models for Human Skeletal Disorders. Front Genet 2021; 12:675331. [PMID: 34490030 PMCID: PMC8418114 DOI: 10.3389/fgene.2021.675331] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 06/08/2021] [Indexed: 12/17/2022] Open
Abstract
In 2019, the Nosology Committee of the International Skeletal Dysplasia Society provided an updated version of the Nosology and Classification of Genetic Skeletal Disorders. This is a reference list of recognized diseases in humans and their causal genes published to help clinician diagnosis and scientific research advances. Complementary to mammalian models, zebrafish has emerged as an interesting species to evaluate chemical treatments against these human skeletal disorders. Due to its versatility and the low cost of experiments, more than 80 models are currently available. In this article, we review the state-of-art of this “aquarium to bedside” approach describing the models according to the list provided by the Nosology Committee. With this, we intend to stimulate research in the appropriate direction to efficiently meet the actual needs of clinicians under the scope of the Nosology Committee.
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Affiliation(s)
- Manuel Marí-Beffa
- Department of Cell Biology, Genetics and Physiology, Faculty of Sciences, University of Málaga, IBIMA, Málaga, Spain.,Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Málaga, Spain
| | - Ana B Mesa-Román
- Department of Cell Biology, Genetics and Physiology, Faculty of Sciences, University of Málaga, IBIMA, Málaga, Spain
| | - Ivan Duran
- Department of Cell Biology, Genetics and Physiology, Faculty of Sciences, University of Málaga, IBIMA, Málaga, Spain.,Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Málaga, Spain
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Koromani F, Alonso N, Alves I, Brandi ML, Foessl I, Formosa MM, Morgenstern MF, Karasik D, Kolev M, Makitie O, Ntzani E, Pietsch BO, Ohlsson C, Rauner M, Soe K, Soldatovic I, Teti A, Valjevac A, Rivadeneira F. The "GEnomics of Musculo Skeletal Traits TranslatiOnal NEtwork": Origins, Rationale, Organization, and Prospects. Front Endocrinol (Lausanne) 2021; 12:709815. [PMID: 34484122 PMCID: PMC8415473 DOI: 10.3389/fendo.2021.709815] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/15/2021] [Indexed: 02/01/2023] Open
Abstract
Musculoskeletal research has been enriched in the past ten years with a great wealth of new discoveries arising from genome wide association studies (GWAS). In addition to the novel factors identified by GWAS, the advent of whole-genome and whole-exome sequencing efforts in family based studies has also identified new genes and pathways. However, the function and the mechanisms by which such genes influence clinical traits remain largely unknown. There is imperative need to bring multidisciplinary expertise together that will allow translating these genomic discoveries into useful clinical applications with the potential of improving patient care. Therefore "GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork" (GEMSTONE) aims to set the ground for the: 1) functional characterization of discovered genes and pathways; 2) understanding of the correspondence between molecular and clinical assessments; and 3) implementation of novel methodological approaches. This research network is funded by The European Cooperation in Science and Technology (COST). GEMSTONE includes six working groups (WG), each with specific objectives: WG1-Study populations and expertise groups: creating, maintaining and updating an inventory of experts and resources (studies and datasets) participating in the network, helping to assemble focus groups defined by phenotype, functional and methodological expertise. WG2-Phenotyping: describe ways to decompose the phenotypes of the different functional studies into meaningful components that will aid the interpretation of identified biological pathways. WG3 Monogenic conditions - human KO models: makes an inventory of genes underlying musculoskeletal monogenic conditions that aids the assignment of genes to GWAS signals and prioritizing GWAS genes as candidates responsible for monogenic presentations, through biological plausibility. WG4 Functional investigations: creating a roadmap of genes and pathways to be prioritized for functional assessment in cell and organism models of the musculoskeletal system. WG5 Bioinformatics seeks the integration of the knowledge derived from the distinct efforts, with particular emphasis on systems biology and artificial intelligence applications. Finally, WG6 Translational outreach: makes a synopsis of the knowledge derived from the distinct efforts, allowing to prioritize factors within biological pathways, use refined disease trait definitions and/or improve study design of future investigations in a potential therapeutic context (e.g. clinical trials) for musculoskeletal diseases.
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Affiliation(s)
- Fjorda Koromani
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands
- Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Nerea Alonso
- Rheumatology and Bone Disease Unit, CGEM-IGMM, University of Edinburgh, Edinburgh, United Kingdom
| | | | - Maria Luisa Brandi
- Department of Surgery and Translational Medicine (M.L.B.), University of Florence, Florence, Italy
| | - Ines Foessl
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Endocrinology Lab Platform, Medical University Graz, Graz, Austria
| | - Melissa M. Formosa
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
| | | | - David Karasik
- Azrieli Faculty of Medicine, Bar-Ilan University, Ramat Gan, Israel
| | - Mikhail Kolev
- Department of Mathematics, South-West University Neofit Rilski, Blagoevgrad, Bulgaria
| | - Outi Makitie
- Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland
| | - Evangelia Ntzani
- Department of Hygiene and Epidemiology, Medical School, University of Ioannina, Ioannina, Greece
- Department of Health Services, Policy and Practice, Center for Research Synthesis in Health, School of Public Health, Brown University, Providence, RI, United States
| | - Barbara Obermayer Pietsch
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Endocrinology Lab Platform, Medical University Graz, Graz, Austria
| | - Claes Ohlsson
- Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Martina Rauner
- Department of Medicine III, Medical Faculty, Technische Universität Dresden, Dresden, Germany
| | - Kent Soe
- Clinical Cell Biology, Department of Pathology, Odense University Hospital, Odense, Denmark
- Clinical Cell Biology, Pathology Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
- Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Ivan Soldatovic
- Institute of Biostatistics, University of Belgrade, Belgrade, Serbia
| | - Anna Teti
- Department of Biotechnological and Applied Clinical Sciences, L’Aquila, Italy
| | - Amina Valjevac
- Department of Physiology, Medical Faculty University of Sarajevo, Sarajevo, Bosnia and Herzegovina
| | - Fernando Rivadeneira
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
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37
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Mäkitie RE, Henning P, Jiu Y, Kämpe A, Kogan K, Costantini A, Välimäki V, Medina‐Gomez C, Pekkinen M, Salusky IB, Schalin‐Jäntti C, Haanpää MK, Rivadeneira F, Bassett JHD, Williams GR, Lerner UH, Pereira RC, Lappalainen P, Mäkitie O. An ARHGAP25 variant links aberrant Rac1 function to early-onset skeletal fragility. JBMR Plus 2021; 5:e10509. [PMID: 34258505 PMCID: PMC8260816 DOI: 10.1002/jbm4.10509] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/10/2021] [Accepted: 04/21/2021] [Indexed: 11/10/2022] Open
Abstract
Ras homologous guanosine triphosphatases (RhoGTPases) control several cellular functions, including cytoskeletal actin remodeling and cell migration. Their activities are downregulated by GTPase-activating proteins (GAPs). Although RhoGTPases are implicated in bone remodeling and osteoclast and osteoblast function, their significance in human bone health and disease remains elusive. Here, we report defective RhoGTPase regulation as a cause of severe, early-onset, autosomal-dominant skeletal fragility in a three-generation Finnish family. Affected individuals (n = 13) presented with multiple low-energy peripheral and vertebral fractures despite normal bone mineral density (BMD). Bone histomorphometry suggested reduced bone volume, low surface area covered by osteoblasts and osteoclasts, and low bone turnover. Exome sequencing identified a novel heterozygous missense variant c.652G>A (p.G218R) in ARHGAP25, encoding a GAP for Rho-family GTPase Rac1. Variants in the ARHGAP25 5' untranslated region (UTR) also associated with BMD and fracture risk in the general population, across multiple genomewide association study (GWAS) meta-analyses (lead variant rs10048745). ARHGAP25 messenger RNA (mRNA) was expressed in macrophage colony-stimulating factor (M-CSF)-stimulated human monocytes and mouse osteoblasts, indicating a possible role for ARHGAP25 in osteoclast and osteoblast differentiation and activity. Studies on subject-derived osteoclasts from peripheral blood mononuclear cells did not reveal robust defects in mature osteoclast formation or resorptive activity. However, analysis of osteosarcoma cells overexpressing the ARHGAP25 G218R-mutant, combined with structural modeling, confirmed that the mutant protein had decreased GAP-activity against Rac1, resulting in elevated Rac1 activity, increased cell spreading, and membrane ruffling. Our findings indicate that mutated ARHGAP25 causes aberrant Rac1 function and consequently abnormal bone metabolism, highlighting the importance of RhoGAP signaling in bone metabolism in familial forms of skeletal fragility and in the general population, and expanding our understanding of the molecular pathways underlying skeletal fragility. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Riikka E. Mäkitie
- Folkhälsan Institute of GeneticsHelsinkiFinland
- Research Program for Clinical and Molecular Metabolism, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Petra Henning
- Department of Internal Medicine and Clinical NutritionCentre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Yaming Jiu
- HiLIFE Institute of BiotechnologyUniversity of HelsinkiHelsinkiFinland
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of ShanghaiChinese Academy of SciencesShanghaiChina
- University of Chinese Academy of SciencesBeijingChina
| | - Anders Kämpe
- Department of Molecular Medicine and Surgery and Center for Molecular MedicineKarolinska InstitutetStockholmSweden
| | - Konstantin Kogan
- HiLIFE Institute of BiotechnologyUniversity of HelsinkiHelsinkiFinland
| | - Alice Costantini
- Department of Molecular Medicine and Surgery and Center for Molecular MedicineKarolinska InstitutetStockholmSweden
| | - Ville‐Valtteri Välimäki
- Department of Orthopaedics and TraumatologyHelsinki University Central Hospital and Helsinki University, Jorvi HospitalEspooFinland
| | - Carolina Medina‐Gomez
- Department of Internal MedicineErasmus MC, University Medical Center RotterdamRotterdamThe Netherlands
| | - Minna Pekkinen
- Folkhälsan Institute of GeneticsHelsinkiFinland
- Research Program for Clinical and Molecular Metabolism, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
| | - Isidro B. Salusky
- Department of PediatricsDavid Geffen School of Medicine at UCLALos AngelesCaliforniaUSA
| | - Camilla Schalin‐Jäntti
- Endocrinology, Abdominal CenterUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - Maria K. Haanpää
- Department of Genomics and Clinical GeneticsTurku University HospitalTurkuFinland
| | - Fernando Rivadeneira
- Department of Internal MedicineErasmus MC, University Medical Center RotterdamRotterdamThe Netherlands
| | - John H. Duncan Bassett
- Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Graham R. Williams
- Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Ulf H. Lerner
- Department of Internal Medicine and Clinical NutritionCentre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of GothenburgGothenburgSweden
| | - Renata C. Pereira
- Department of PediatricsDavid Geffen School of Medicine at UCLALos AngelesCaliforniaUSA
| | - Pekka Lappalainen
- HiLIFE Institute of BiotechnologyUniversity of HelsinkiHelsinkiFinland
| | - Outi Mäkitie
- Folkhälsan Institute of GeneticsHelsinkiFinland
- Research Program for Clinical and Molecular Metabolism, Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
- Department of Molecular Medicine and Surgery and Center for Molecular MedicineKarolinska InstitutetStockholmSweden
- Children's HospitalUniversity and Helsinki University HospitalHelsinkiFinland
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38
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Claeys L, Storoni S, Eekhoff M, Elting M, Wisse L, Pals G, Bravenboer N, Maugeri A, Micha D. Collagen transport and related pathways in Osteogenesis Imperfecta. Hum Genet 2021; 140:1121-1141. [PMID: 34169326 PMCID: PMC8263409 DOI: 10.1007/s00439-021-02302-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/08/2021] [Indexed: 12/16/2022]
Abstract
Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although collagen type I defects are long established as the primary cause of the bone pathology, we are still far from comprehending the complete mechanism. In the last years, the advent of next generation sequencing has triggered the discovery of many new genetic causes for OI, helping to draw its molecular landscape. It has become clear that, in addition to collagen type I genes, OI can be caused by multiple proteins connected to different parts of collagen biosynthesis. The production of collagen entails a complex process, starting from the production of the collagen Iα1 and collagen Iα2 chains in the endoplasmic reticulum, during and after which procollagen is subjected to a plethora of posttranslational modifications by chaperones. After reaching the Golgi organelle, procollagen is destined to the extracellular matrix where it forms collagen fibrils. Recently discovered mutations in components of the retrograde transport of chaperones highlight its emerging role as critical contributor of OI development. This review offers an overview of collagen regulation in the context of recent gene discoveries, emphasizing the significance of transport disruptions in the OI mechanism. We aim to motivate exploration of skeletal fragility in OI from the perspective of these pathways to identify regulatory points which can hint to therapeutic targets.
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Affiliation(s)
- Lauria Claeys
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Silvia Storoni
- Department of Internal Medicine Section Endocrinology, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Marelise Eekhoff
- Department of Internal Medicine Section Endocrinology, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Mariet Elting
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Lisanne Wisse
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Gerard Pals
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Nathalie Bravenboer
- Department of Clinical Chemistry, Amsterdam /UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Alessandra Maugeri
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Dimitra Micha
- Department of Clinical Genetics, Amsterdam UMC, Amsterdam Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
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39
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Fédou C, Camus M, Lescat O, Feuillet G, Mueller I, Ross B, Buléon M, Neau E, Alves M, Goudounéche D, Breuil B, Boizard F, Bardou Q, Casemayou A, Tack I, Dreux S, Batut J, Blader P, Burlet-Schiltz O, Decramer S, Wirth B, Klein J, Saulnier-Blache JS, Buffin-Meyer B, Schanstra JP. Mapping of the amniotic fluid proteome of fetuses with congenital anomalies of the kidney and urinary tract identifies plastin 3 as a protein involved in glomerular integrity. J Pathol 2021; 254:575-588. [PMID: 33987838 DOI: 10.1002/path.5703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/04/2021] [Accepted: 05/10/2021] [Indexed: 11/07/2022]
Abstract
Congenital anomalies of the kidney and the urinary tract (CAKUT) are the first cause of chronic kidney disease in childhood. Several genetic and environmental origins are associated with CAKUT, but most pathogenic pathways remain elusive. Considering the amniotic fluid (AF) composition as a proxy for fetal kidney development, we analyzed the AF proteome from non-severe CAKUT (n = 19), severe CAKUT (n = 14), and healthy control (n = 22) fetuses using LC-MS/MS. We identified 471 significant proteins that discriminated the three AF groups with 81% precision. Among them, eight proteins independent of gestational age (CSPG4, LMAN2, ENDOD1, ANGPTL2, PRSS8, NGFR, ROBO4, PLS3) were associated with both the presence and the severity of CAKUT. Among those, five were part of a protein-protein interaction network involving proteins previously identified as being potentially associated with CAKUT. The actin-bundling protein PLS3 (plastin 3) was the only protein displaying a gradually increased AF abundance from control, via non-severe, to severe CAKUT. Immunohistochemistry experiments showed that PLS3 was expressed in the human fetal as well as in both the fetal and the postnatal mouse kidney. In zebrafish embryos, depletion of PLS3 led to a general disruption of embryonic growth including reduced pronephros development. In postnatal Pls3-knockout mice, kidneys were macroscopically normal, but the glomerular ultrastructure showed thickening of the basement membrane and fusion of podocyte foot processes. These structural changes were associated with albuminuria and decreased expression of podocyte markers including Wilms' tumor-1 protein, nephrin, and podocalyxin. In conclusion, we provide the first map of the CAKUT AF proteome that will serve as a reference for future studies. Among the proteins strongly associated with CAKUT, PLS3 did surprisingly not specifically affect nephrogenesis but was found as a new contributor in the maintenance of normal kidney function, at least in part through the control of glomerular integrity. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Camille Fédou
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Mylène Camus
- Institut de Pharmacologie et Biologie Structurale (IPBS), Université de Toulouse, UPS, CNRS, Toulouse, France
| | - Ophélie Lescat
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Guylène Feuillet
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Ilka Mueller
- Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute for Genetics, and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany
| | - Bryony Ross
- Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute for Genetics, and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany
| | - Marie Buléon
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Eric Neau
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Melinda Alves
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Dominique Goudounéche
- Centre de Microscopie Electronique Appliquée à la Biologie (CMEAB), Faculté de Médecine Rangueil, University of Toulouse, Toulouse, France
| | - Benjamin Breuil
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Franck Boizard
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Quentin Bardou
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Audrey Casemayou
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France.,Département de Néphrologie et Transplantation d'Organes, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Ivan Tack
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Sophie Dreux
- Unité de Biochimie Fœto-Placentaire, Laboratoire de Biochimie - Hormonologie CHU Robert Debré, AP-HP, Paris, France
| | - Julie Batut
- Molecular, Cellular and Developmental Biology Unit (MCD, UMR5077), Centre de Biologie Intégrative (CBI, FR3743), Université de Toulouse, Toulouse, France
| | - Patrick Blader
- Molecular, Cellular and Developmental Biology Unit (MCD, UMR5077), Centre de Biologie Intégrative (CBI, FR3743), Université de Toulouse, Toulouse, France
| | - Odile Burlet-Schiltz
- Institut de Pharmacologie et Biologie Structurale (IPBS), Université de Toulouse, UPS, CNRS, Toulouse, France
| | - Stéphane Decramer
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France.,Service de Néphrologie Pédiatrique, Hôpital des Enfants, CHU Toulouse, Toulouse, France.,Centre De Référence des Maladies Rénales Rares du Sud-Ouest (SORARE), Toulouse, France
| | - Brunhilde Wirth
- Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute for Genetics, and Center for Rare Diseases Cologne, University of Cologne, Cologne, Germany
| | - Julie Klein
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Jean Sébastien Saulnier-Blache
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Bénédicte Buffin-Meyer
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Joost P Schanstra
- Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
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40
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Plastin 3 in health and disease: a matter of balance. Cell Mol Life Sci 2021; 78:5275-5301. [PMID: 34023917 PMCID: PMC8257523 DOI: 10.1007/s00018-021-03843-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/06/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023]
Abstract
For a long time, PLS3 (plastin 3, also known as T-plastin or fimbrin) has been considered a rather inconspicuous protein, involved in F-actin-binding and -bundling. However, in recent years, a plethora of discoveries have turned PLS3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases. PLS3 is localized on the X-chromosome, but shows sex-specific, inter-individual and tissue-specific expression variability pointing towards skewed X-inactivation. PLS3 is expressed in all solid tissues but usually not in hematopoietic cells. When escaping X-inactivation, PLS3 triggers a plethora of different types of cancers. Elevated PLS3 levels are considered a prognostic biomarker for cancer and refractory response to therapies. When it is knocked out or mutated in humans and mice, it causes osteoporosis with bone fractures; it is the only protein involved in actin dynamics responsible for osteoporosis. Instead, when PLS3 is upregulated, it acts as a highly protective SMN-independent modifier in spinal muscular atrophy (SMA). Here, it seems to counteract reduced F-actin levels by restoring impaired endocytosis and disturbed calcium homeostasis caused by reduced SMN levels. In contrast, an upregulation of PLS3 on wild-type level might cause osteoarthritis. This emphasizes that the amount of PLS3 in our cells must be precisely balanced; both too much and too little can be detrimental. Actin-dynamics, regulated by PLS3 among others, are crucial in a lot of cellular processes including endocytosis, cell migration, axonal growth, neurotransmission, translation, and others. Also, PLS3 levels influence the infection with different bacteria, mycosis, and other pathogens.
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41
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Caetano da Silva C, Ricquebourg M, Orcel P, Fabre S, Funck‐Brentano T, Cohen‐Solal M, Collet C. More severe phenotype of early-onset osteoporosis associated with recessive form of LRP5 and combination with DKK1 or WNT3A. Mol Genet Genomic Med 2021; 9:e1681. [PMID: 33939331 PMCID: PMC8222848 DOI: 10.1002/mgg3.1681] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 03/23/2021] [Indexed: 12/13/2022] Open
Abstract
Background Early‐onset osteoporosis (EOOP) is defined by low bone mineral density (BMD), which increases the risk of fracture. Although the prevalence of osteoporosis at a young age is unknown, low BMD is highly linked to genetic background. Heterozygous pathogenic variants in low‐density lipoprotein receptor‐related protein 5 (LRP5) are associated with EOOP. This study aimed to investigate the genetic profile in patients with EOOP to better understand the variation in phenotype severity by using a targeted gene sequencing panel associated with bone fragility. Method and Results We used a sequencing panel with 17 genes reported to be related to bone fragility for analysis of 68 patients with EOOP. We found a high positivity rate of EOOP with LRP5 variants (14 patients, 20.6%). The remaining 79.4% of patients with EOOP but without LRP5 variants showed variable disease severity, as observed in patients with at least one variant in this gene. One patient, with multiple fractures and spine L1‐L4 BMD Z‐score −2.9, carried a novel pathogenic homozygous variant, c.2918T>C, p.(Leu973Pro), without any pseudoglioma. In addition to carrying the LRP5 variant, 2 other patients carried a heterozygous variant in Wnt signaling pathway genes: dickkopf WNT signaling pathway inhibitor 1 (DKK1) [NM_012242.4: c.359G>T, p.(Arg120Leu)] and Wnt family member 3A (WNT3A) [NM_033131.3: c.377G>A, p. (Arg126His)]. As compared with single‐variant LRP5 carriers, double‐variant carriers had a significantly lower BMD Z‐score (−4.1 ± 0.8) and higher mean number of fractures (6.0 ± 2.8 vs. 2.2 ± 1.9). Analysis of the family segregation suggests the inheritance of BMD trait. Conclusion Severe forms of EOOP may occur with carriage of 2 pathogenic variants in genes encoding regulators of the Wnt signaling pathway. Two‐variant carriers of Wnt pathway genes had severe EOOP. Moreover, DKK1 and WNT3A genes should be included in next‐generation sequence analyses of bone fragility. Gene association may occur in the same signaling pathway and can generate a severe bone phenotype in early‐onset osteoporosis. Recessive form associated with lipoprotein receptor‐related protein 5 could be responsible for a stronger phenotype. Interestingly this recessive form is not associated with ocular problems as observed in pseudoglioma osteoporosis or vitreoretinopathy. Assessment of genetics based on an next generation sequencing panel should include WNT3A and DKK1.
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Affiliation(s)
| | - Manon Ricquebourg
- Inserm U1132 and Université de ParisParisFrance
- Department of RheumatologyHôpital Lariboisière, AP‐HPParisFrance
| | - Philippe Orcel
- Inserm U1132 and Université de ParisParisFrance
- Department of RheumatologyHôpital Lariboisière, AP‐HPParisFrance
| | - Stéphanie Fabre
- Inserm U1132 and Université de ParisParisFrance
- Department of RheumatologyHôpital Lariboisière, AP‐HPParisFrance
| | - Thomas Funck‐Brentano
- Inserm U1132 and Université de ParisParisFrance
- Department of RheumatologyHôpital Lariboisière, AP‐HPParisFrance
| | - Martine Cohen‐Solal
- Inserm U1132 and Université de ParisParisFrance
- Department of RheumatologyHôpital Lariboisière, AP‐HPParisFrance
| | - Corinne Collet
- Inserm U1132 and Université de ParisParisFrance
- Functional Unit of Molecular BiologyHôpital Lariboisière, AP‐HPParisFrance
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Fratzl-Zelman N, Wesseling-Perry K, Mäkitie RE, Blouin S, Hartmann MA, Zwerina J, Välimäki VV, Laine CM, Välimäki MJ, Pereira RC, Mäkitie O. Bone material properties and response to teriparatide in osteoporosis due to WNT1 and PLS3 mutations. Bone 2021; 146:115900. [PMID: 33618074 DOI: 10.1016/j.bone.2021.115900] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/11/2021] [Accepted: 02/15/2021] [Indexed: 12/22/2022]
Abstract
CONTEXT Patients with osteoporosis-associated WNT1 or PLS3 mutations have unique bone histomorphometric features and osteocyte-specific hormone expression patterns. OBJECTIVE To investigate the effects of WNT1 and PLS3 mutations on bone material properties. DESIGN Transiliac bone biopsies were evaluated by quantitative backscattered electron imaging, immunohistochemistry, and bone histomorphometry. SETTING Ambulatory patients. PATIENTS Three pediatric and eight adult patients with WNT1 or PLS3 mutations. INTERVENTION Bone mineralization density distribution and osteocyte protein expression was evaluated in 11 patients and repeated in six patients who underwent repeat biopsy after 24 months of teriparatide treatment. MAIN OUTCOME MEASURE Bone mineralization density distribution and protein expression. RESULTS Children with WNT1 or PLS3 mutations had heterogeneous bone matrix mineralization, consistent with bone modeling during growth. Bone matrix mineralization was homogenous in adults and increased throughout the age spectrum. Teriparatide had very little effect on matrix mineralization or bone formation in patients with WNT1 or PLS3 mutations. However, teriparatide decreased trabecular osteocyte lacunae size and increased trabecular bone FGF23 expression. CONCLUSION The contrast between preserved bone formation with heterogeneous mineralization in children and low bone turnover with homogenous bone mineral content in adults suggests that WNT1 and PLS3 have differential effects on bone modeling and remodeling. The lack of change in matrix mineralization in response to teriparatide, despite clear changes in osteocyte lacunae size and protein expression, suggests that altered WNT1 and PLS3 expression may interfere with coupling of osteocyte, osteoblast, and osteoclast function. Further studies are warranted to determine the mechanism of these changes.
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Affiliation(s)
- Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | | | - Riikka E Mäkitie
- Folkhälsan Institute of Genetics and University of Helsinki, Helsinki, Finland
| | - Stéphane Blouin
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Markus A Hartmann
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Jochen Zwerina
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Ville-Valtteri Välimäki
- Department of Orthopaedics and Traumatology, Helsinki University Central Hospital and Helsinki University, Jorvi Hospital, Espoo, Finland
| | - Christine M Laine
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Endocrinology, Institute of Medicine, Sahlgrenska University Hospital and University of Gothenburg, Gothenburg, Sweden
| | - Matti J Välimäki
- Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
| | - Renata C Pereira
- Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Outi Mäkitie
- Folkhälsan Institute of Genetics and University of Helsinki, Helsinki, Finland; Department of Orthopedics, Institute of Clinical Sciences, Sahlgrenska University Hospital and University of Gothenburg, Gothenburg, Sweden; Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Molecular Medicine and Surgery, Karolinska Institutet and Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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43
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Grillari J, Mäkitie RE, Kocijan R, Haschka J, Vázquez DC, Semmelrock E, Hackl M. Circulating miRNAs in bone health and disease. Bone 2021; 145:115787. [PMID: 33301964 DOI: 10.1016/j.bone.2020.115787] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/27/2020] [Accepted: 12/01/2020] [Indexed: 12/15/2022]
Abstract
microRNAs have evolved as important regulators of multiple biological pathways essential for bone homeostasis, and microRNA research has furthered our understanding of the mechanisms underlying bone health and disease. This knowledge, together with the finding that active or passive release of microRNAs from cells into the extracellular space enables minimal-invasive detection in biofluids (circulating miRNAs), motivated researchers to explore microRNAs as biomarkers in several pathologic conditions, including bone diseases. Thus, exploratory studies in cohorts representing different types of bone diseases have been performed. In this review, we first summarize important molecular basics of microRNA function and release and provide recommendations for best (pre-)analytical practices and documentation standards for circulating microRNA research required for generating high quality data and ensuring reproducibility of results. Secondly, we review how the genesis of bone-derived circulating microRNAs via release from osteoblasts and osteoclasts could contribute to the communication between these cells. Lastly, we summarize evidence from clinical research studies that have investigated the clinical utility of microRNAs as biomarkers in musculoskeletal disorders. While previous reviews have mainly focused on diagnosis of primary osteoporosis, we have also included studies exploring the utility of circulating microRNAs in monitoring anti-osteoporotic treatment and for diagnosis of other types of bone diseases, such as diabetic osteopathy, bone degradation in inflammatory diseases, and monogenetic bone diseases.
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Affiliation(s)
- Johannes Grillari
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria; Institute for Molecular Biotechnology, BOKU - University of Natural Resources and Life Sciences, Vienna, Austria; Austrian Cluster for Tissue Regeneration, Austria
| | - Riikka E Mäkitie
- Folkhälsan Institute of Genetics and University of Helsinki, Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Molecular Endocrinology Laboratory, Department of Medicine, Hammersmith Campus, Imperial College London, London, United Kingdom
| | - Roland Kocijan
- Hanusch Hospital of the WGKK and AUVA Trauma Center, 1st Medical Department at Hanusch Hospital, Ludwig Boltzmann Institute of Osteology, Vienna, Austria; Sigmund Freud University Vienna, School of Medicine, Metabolic Bone Diseases Unit, Austria
| | - Judith Haschka
- Hanusch Hospital of the WGKK and AUVA Trauma Center, 1st Medical Department at Hanusch Hospital, Ludwig Boltzmann Institute of Osteology, Vienna, Austria; Karl Landsteiner Institute for Rheumatology and Gastroenterology, Vienna, Austria
| | | | | | - Matthias Hackl
- Austrian Cluster for Tissue Regeneration, Austria; TAmiRNA GmbH, Vienna, Austria.
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Expression and Localization of Thrombospondins, Plastin 3, and STIM1 in Different Cartilage Compartments of the Osteoarthritic Varus Knee. Int J Mol Sci 2021; 22:ijms22063073. [PMID: 33802838 PMCID: PMC8002632 DOI: 10.3390/ijms22063073] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/13/2021] [Accepted: 03/15/2021] [Indexed: 02/08/2023] Open
Abstract
Osteoarthritis (OA) is a multifactorial disease which is characterized by a change in the homeostasis of the extracellular matrix (ECM). The ECM is essential for the function of the articular cartilage and plays an important role in cartilage mechanotransduction. To provide a better understanding of the interaction between the ECM and the actin cytoskeleton, we investigated the localization and expression of the Ca2+-dependent proteins cartilage oligomeric matrix protein (COMP), thrombospondin-1 (TSP-1), plastin 3 (PLS3) and stromal interaction molecule 1 (STIM1). We investigated 16 patients who suffered from varus knee OA and performed a topographical analysis of the cartilage from the medial and lateral compartment of the proximal tibial plateau. In a varus knee, OA is more pronounced in the medial compared to the lateral compartment as a result of an overloading due to the malalignment. We detected a location-dependent staining of PLS3 and STIM1 in the articular cartilage tissue. The staining intensity for both proteins correlated with the degree of cartilage degeneration. The staining intensity of TSP-1 was clearly reduced in the cartilage of the more affected medial compartment, an observation that was confirmed in cartilage extracts by immunoblotting. The total amount of COMP was unchanged; however, slight changes were detected in the localization of the protein. Our results provide novel information on alterations in OA cartilage suggesting that Ca2+-dependent mechanotransduction between the ECM and the actin cytoskeleton might play an essential role in the pathomechanism of OA.
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45
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McInerney-Leo AM, Duncan EL. Massively Parallel Sequencing for Rare Genetic Disorders: Potential and Pitfalls. Front Endocrinol (Lausanne) 2021; 11:628946. [PMID: 33679611 PMCID: PMC7933540 DOI: 10.3389/fendo.2020.628946] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/21/2020] [Indexed: 01/04/2023] Open
Abstract
There have been two major eras in the history of gene discovery. The first was the era of linkage analysis, with approximately 1,300 disease-related genes identified by positional cloning by the turn of the millennium. The second era has been powered by two major breakthroughs: the publication of the human genome and the development of massively parallel sequencing (MPS). MPS has greatly accelerated disease gene identification, such that disease genes that would have taken years to map previously can now be determined in a matter of weeks. Additionally, the number of affected families needed to map a causative gene and the size of such families have fallen: de novo mutations, previously intractable by linkage analysis, can be identified through sequencing of the parent-child trio, and genes for recessive disease can be identified through MPS even of a single affected individual. MPS technologies include whole exome sequencing (WES), whole genome sequencing (WGS), and panel sequencing, each with their strengths. While WES has been responsible for most gene discoveries through MPS, WGS is superior in detecting copy number variants, chromosomal rearrangements, and repeat-rich regions. Panels are commonly used for diagnostic purposes as they are extremely cost-effective and generate manageable quantities of data, with no risk of unexpected findings. However, in instances of diagnostic uncertainty, it can be challenging to choose the right panel, and in these circumstances WES has a higher diagnostic yield. MPS has ethical, social, and legal implications, many of which are common to genetic testing generally but amplified due to the magnitude of data (e.g., relationship misattribution, identification of variants of uncertain significance, and genetic discrimination); others are unique to WES and WGS technologies (e.g., incidental or secondary findings). Nonetheless, MPS is rapidly translating into clinical practice as an extremely useful part of the clinical armamentarium.
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Affiliation(s)
- Aideen M. McInerney-Leo
- Dermatology Research Centre, University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Emma L. Duncan
- Department of Twin Research & Genetic Epidemiology, Faculty of Life Sciences and Medicine, School of Life Course Sciences, King’s College London, London, United Kingdom
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46
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Schwebach CL, Kudryashova E, Kudryashov DS. Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca 2+-Dependent Regulation Is Equivalent to Protein Loss. Front Cell Dev Biol 2021; 8:635783. [PMID: 33553175 PMCID: PMC7859272 DOI: 10.3389/fcell.2020.635783] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 12/28/2020] [Indexed: 12/14/2022] Open
Abstract
Osteogenesis imperfecta is a genetic disorder disrupting bone development and remodeling. The primary causes of osteogenesis imperfecta are pathogenic variants of collagen and collagen processing genes. However, recently variants of the actin bundling protein plastin 3 have been identified as another source of osteogenesis imperfecta. Plastin 3 is a highly conserved protein involved in several important cellular structures and processes and is controlled by intracellular Ca2+ which potently inhibits its actin-bundling activity. The precise mechanisms by which plastin 3 causes osteogenesis imperfecta remain unclear, but recent advances have contributed to our understanding of bone development and the actin cytoskeleton. Here, we review the link between plastin 3 and osteogenesis imperfecta highlighting in vitro studies and emphasizing the importance of Ca2+ regulation in the localization and functionality of plastin 3.
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Affiliation(s)
- Christopher L Schwebach
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, United States
| | - Elena Kudryashova
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, United States
| | - Dmitri S Kudryashov
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, United States
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47
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Wirth B. Spinal Muscular Atrophy: In the Challenge Lies a Solution. Trends Neurosci 2021; 44:306-322. [PMID: 33423791 DOI: 10.1016/j.tins.2020.11.009] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/08/2020] [Accepted: 11/30/2020] [Indexed: 12/16/2022]
Abstract
The path from gene discovery to therapy in spinal muscular atrophy (SMA) has been a highly challenging endeavor, but also led to one of the most successful stories in neurogenetics. In SMA, a neuromuscular disorder with an often fatal outcome until recently, with those affected never able to sit, stand, or walk, children now achieve these motoric abilities and almost age-based development when treated presymptomatically. This review summarizes the challenges along this 30-year journey. It is also meant to inspire early-career scientists not to give up when things become difficult but to try to uncover the biological underpinnings and transform the challenge into the next big discovery. Without doubt, the improvements seen with the three therapeutic strategies in SMA are impressive; many open questions remain and are discussed in this review.
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Affiliation(s)
- Brunhilde Wirth
- Institute of Human Genetics, Center for Molecular Medicine, Center for Rare Disorders, University of Cologne, Kerpener Str. 34, 50931 Cologne, Germany.
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48
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Sharma A, Sharma L, Goyal R. Molecular Signaling Pathways and Essential Metabolic Elements in Bone Remodeling: An Implication of Therapeutic Targets for Bone Diseases. Curr Drug Targets 2020; 22:77-104. [PMID: 32914712 DOI: 10.2174/1389450121666200910160404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 06/28/2020] [Accepted: 07/15/2020] [Indexed: 01/01/2023]
Abstract
Bone is one of the dynamic tissues in the human body that undergoes continuous remodelling through subsequent actions of bone cells, osteoclasts, and osteoblasts. Several signal transduction pathways are involved in the transition of mesenchymal stem cells into osteoblasts. These primarily include Runx2, ATF4, Wnt signaling and sympathetic signalling. The differentiation of osteoclasts is controlled by M-CSF, RANKL, and costimulatory signalling. It is well known that bone remodelling is regulated through receptor activator of nuclear factor-kappa B ligand followed by binding to RANK, which eventually induces the differentiation of osteoclasts. The resorbing osteoclasts secrete TRAP, cathepsin K, MMP-9 and gelatinase to digest the proteinaceous matrix of type I collagen and form a saucer-shaped lacuna along with resorption tunnels in the trabecular bone. Osteoblasts secrete a soluble decoy receptor, osteoprotegerin that prevents the binding of RANK/RANKL and thus moderating osteoclastogenesis. Moreover, bone homeostasis is also regulated by several growth factors like, cytokines, calciotropic hormones, parathyroid hormone and sex steroids. The current review presents a correlation of the probable molecular targets underlying the regulation of bone mass and the role of essential metabolic elements in bone remodelling. Targeting these signaling pathways may help to design newer therapies for treating bone diseases.
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Affiliation(s)
- Aditi Sharma
- School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173212, India
| | - Lalit Sharma
- School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173212, India
| | - Rohit Goyal
- School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173212, India
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49
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Hu J, Li LJ, Zheng WB, Zhao DC, Wang O, Jiang Y, Xing XP, Li M, Xia W. A novel mutation in PLS3 causes extremely rare X-linked osteogenesis imperfecta. Mol Genet Genomic Med 2020; 8:e1525. [PMID: 33166085 PMCID: PMC7767536 DOI: 10.1002/mgg3.1525] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/03/2020] [Accepted: 09/17/2020] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous bone disease characterized by bone fragility and recurrent fractures. X-linked inherited OI with mutation in PLS3 is so rare that its genotype-phenotype characteristics are not available. METHODS We designed a novel targeted next-generation sequencing (NGS) panel with the candidate genes of OI to detect pathogenic mutations and confirmed them by Sanger sequencing. The phenotypes of the patients were also investigated. RESULTS The proband, a 12-year-old boy from a nonconsanguineous family, experienced multiple fractures of long bones and vertebrae and had low bone mineral density (BMD Z-score of -3.2 to -2.0). His younger brother also had extremity fractures. A novel frameshift mutation (c.1106_1107insGAAA; p.Phe369Leufs*5) in exon 10 of PLS3 was identified in the two patients, which was inherited from their mother who had normal BMD. Blue sclerae were the only extraskeletal symptom in all affected individuals. Zoledronic acid was beneficial for increasing BMD and reshaping the compressed vertebral bodies of the proband. CONCLUSION We first identify a novel mutation in PLS3 that led to rare X-linked OI and provide practical information for the diagnosis and treatment of this disease.
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Affiliation(s)
- Jing Hu
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lu-Jiao Li
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of Endocrinology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wen-Bin Zheng
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Di-Chen Zhao
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ou Wang
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Jiang
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiao-Ping Xing
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mei Li
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weibo Xia
- Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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50
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Rocha-Braz MGM, França MM, Fernandes AM, Lerario AM, Zanardo EA, de Santana LS, Kulikowski LD, Martin RM, Mendonca BB, Ferraz-de-Souza B. Comprehensive Genetic Analysis of 128 Candidate Genes in a Cohort With Idiopathic, Severe, or Familial Osteoporosis. J Endocr Soc 2020; 4:bvaa148. [PMID: 33195954 PMCID: PMC7645613 DOI: 10.1210/jendso/bvaa148] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 09/29/2020] [Indexed: 12/31/2022] Open
Abstract
Context The genetic bases of osteoporosis (OP), a disorder with high heritability, are poorly understood at an individual level. Cases of idiopathic or familial OP have long puzzled clinicians as to whether an actionable genetic cause could be identified. Objective We performed a genetic analysis of 28 cases of idiopathic, severe, or familial osteoporosis using targeted massively parallel sequencing. Design Targeted sequencing of 128 candidate genes was performed using Illumina NextSeq. Variants of interest were confirmed by Sanger sequencing or SNP array. Patients and Setting Thirty-seven patients in an academic tertiary hospital participated (54% male; median age, 44 years; 86% with fractures), corresponding to 28 sporadic or familial cases. Main Outcome Measure The identification of rare stop-gain, indel, splice site, copy-number, or nonsynonymous variants altering protein function. Results Altogether, we identified 28 variants of interest, but only 3 were classified as pathogenic or likely pathogenic variants: COL1A2 p.(Arg708Gln), WNT1 p.(Gly169Asp), and IDUA p.(His82Gln). An association of variants in different genes was found in 21% of cases, including a young woman with severe OP bearing WNT1, PLS3, and NOTCH2 variants. Among genes of uncertain significance analyzed, a potential additional line of evidence has arisen for GWAS candidates GPR68 and NBR1, warranting further studies. Conclusions While we hope that continuing efforts to identify genetic predisposition to OP will lead to improved and personalized care in the future, the likelihood of identifying actionable pathogenic variants in intriguing cases of idiopathic or familial osteoporosis is seemingly low.
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Affiliation(s)
- Manuela G M Rocha-Braz
- Laboratorio de Endocrinologia Celular e Molecular LIM-25, Divisao de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Monica M França
- Laboratorio de Hormonios e Genetica Molecular LIM-42, Divisao de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.,The University of Chicago, Department of Medicine, Section of Endocrinology, Chicago, Illinois USA
| | - Adriana M Fernandes
- Laboratorio de Endocrinologia Celular e Molecular LIM-25, Divisao de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Antonio M Lerario
- Laboratorio de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.,Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan, USA
| | - Evelin A Zanardo
- Laboratorio de Citogenomica, Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Lucas S de Santana
- Laboratorio de Endocrinologia Celular e Molecular LIM-25, Divisao de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Leslie D Kulikowski
- Laboratorio de Citogenomica, Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil
| | - Regina M Martin
- Laboratorio de Hormonios e Genetica Molecular LIM-42, Divisao de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Berenice B Mendonca
- Laboratorio de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Bruno Ferraz-de-Souza
- Laboratorio de Endocrinologia Celular e Molecular LIM-25, Divisao de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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