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Tan Z, Shek HT, Li Z, Xia L, He Y, Chen P, Wong JSH, Gao B, Chan D, To MKT. An inducible mouse model of osteogenesis imperfecta type V reveals aberrant osteogenesis caused by Ifitm5 c.-14C>T mutation. J Bone Miner Res 2025; 40:577-590. [PMID: 39908237 PMCID: PMC12103725 DOI: 10.1093/jbmr/zjaf022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 01/14/2025] [Accepted: 01/18/2025] [Indexed: 02/07/2025]
Abstract
Osteogenesis imperfecta (OI) type V is typically characterized by radial head dislocation, calcification of interosseous membrane, and hyperplastic callus. It is caused by the c.-14C>T mutation in the 5' UTR of IFITM5 gene, adding 5 amino acids (MALEP) to the N-terminal of IFITM5 protein. Previous studies have suggested a neomorphic function of the MALEP-IFITM5 protein. However, the underlying mechanisms remain unclear due to embryonic lethality in previous mouse models. Therefore, we developed an inducible mouse model (Ifitm5flox c.-14C>T) that could be induced by Cre expressed at different developmental stages to explore the pathogenic effects of the neomorphic MALEP-IFITM5. The mutant Ifitm5 allele could be regulated by the endogenous regulatory elements after Cre recombination, maintaining its spatiotemporal expression pattern and physiological level. Specifically, Prx1-Cre; Ifitm5flox c.-14C>T mutant mice were born with fractures in all limbs, showing impaired ossification and enhanced chondrogenesis associated with increased SOX9 abundance. Analyses of single-cell RNA sequencing data revealed arrested osteogenesis in Prx1-Cre; Ifitm5flox c.-14C>T mouse. A major population of cells expressing both osteogenic and chondrogenic signature genes was identified in the mutant mouse. Reduced expression of SP7 and SOST in the cortical regions of mutant mice confirmed delayed osteocyte maturation and compromised osteogenesis. Elevated bone marrow adipocytes were found in the adult mutant mice. Ectopic chondrogenesis and SOX9 expression were also observed in the perichondrium regions of Col1a1-Cre; Ifitm5flox c.-14C>T and Ocn-Cre; Ifitm5flox c.-14C>T mutant mice. The inducible Ifitm5flox c.-14C>T mouse model and integrated single-cell transcriptomic analyses elucidated that ectopic expression of SOX9 and disrupted homeostatic balance among osteogenesis, chondrogenesis, and adipogenesis may contribute to the pathogenesis caused by MALEP-IFITM5, helping to gain deeper insights into the molecular mechanisms of type V OI.
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Affiliation(s)
- Zhijia Tan
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- Shenzhen Clinical Research Centre for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hiu Tung Shek
- Shenzhen Clinical Research Centre for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Zeluan Li
- Shenzhen Clinical Research Centre for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Linjian Xia
- Clinical, Translational and Basic Research Laboratory, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
| | - Yanni He
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- Shenzhen Clinical Research Centre for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
| | - Peikai Chen
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- Shenzhen Clinical Research Centre for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Janus Siu Him Wong
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- Shenzhen Clinical Research Centre for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Bo Gao
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Danny Chan
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Michael Kai Tsun To
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- Shenzhen Clinical Research Centre for Rare Diseases, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China
- Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Reinoso Gomezcoello MF, Pavón de Paz I, Navea Aguilera C, Gil Fournier B, Bueno Sanchez AM, Guijarro de Armas G, Merino Viveros M, Rosado Sierra JA, Iglesias Bolaños P, Durán Martínez M. Osteogenesis imperfecta type V: About a clinical case. ENDOCRINOL DIAB NUTR 2025; 72:501544. [PMID: 40379599 DOI: 10.1016/j.endien.2025.501544] [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: 08/06/2024] [Revised: 11/21/2024] [Accepted: 11/23/2024] [Indexed: 05/19/2025]
Abstract
Osteogenesis imperfecta (OI) is a rare inherited connective tissue disorder. It is characterized by short stature, fragility and decreased bone mass, which leads to multiple and recurrent fractures after low-energy trauma, which generates susceptibility to long bone deformity and vertebral compression. There are several types of OI, with types I to IV, in which the COL1A1 and COL1A2 genes are affected, being the most frequent. In recent years, the discovery of new forms of OI has led to research into the pathways critical aspects of bone metabolism, with new genes involved being identified. The mutation in IFITM5 has been identified as the cause of OI type V, of autosomal dominant inheritance. OI type V has distinctive clinical features including the development of hypertrophic callus after fracture, early calcification of the interosseous membrane in the forearm, and the presence of hyperdense metaphyseal bands. The case of a patient with a novo mutation in IFITM5 is presented.
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Affiliation(s)
| | - Isabel Pavón de Paz
- Servicio de Endocrinología y Nutrición, Hospital Universitario de Getafe, Getafe, Madrid, Spain
| | - Cristina Navea Aguilera
- Servicio de Endocrinología y Nutrición, Hospital Universitario de Getafe, Getafe, Madrid, Spain
| | - Belén Gil Fournier
- Departamento de Genética, Hospital Universitario de Getafe, Getafe, Madrid, Spain
| | - Ana María Bueno Sanchez
- Servicio de Cirugía Ortopédica y Traumatología, Hospital Universitario de Getafe, Getafe, Madrid, Spain
| | | | - María Merino Viveros
- Servicio de Endocrinología y Nutrición, Hospital Universitario de Getafe, Getafe, Madrid, Spain
| | | | - Paloma Iglesias Bolaños
- Servicio de Endocrinología y Nutrición, Hospital Universitario de Getafe, Getafe, Madrid, Spain
| | - María Durán Martínez
- Servicio de Endocrinología y Nutrición, Hospital Universitario de Getafe, Getafe, Madrid, Spain
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Chaugule S, Constantinou CK, John AA, Micha D, Eekhoff M, Gravallese E, Gao G, Shim JH. Comprehensive Review of Osteogenesis Imperfecta: Current Treatments and Future Innovations. Hum Gene Ther 2025; 36:597-617. [PMID: 39932815 PMCID: PMC11971546 DOI: 10.1089/hum.2024.191] [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: 10/17/2024] [Accepted: 01/08/2025] [Indexed: 02/13/2025] Open
Abstract
Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility due to reduced bone quality, often accompanied by low bone mass, recurrent fractures, hearing loss, skeletal abnormalities, and short stature. Pathogenic variants in over 20 genes lead to clinical and genetic variability in OI, resulting in diverse symptoms and severity. Current management involves a multidisciplinary approach, including antiresorptive medications, physiotherapy, occupational therapy, and orthopedic surgery, which provide symptomatic relief but no cure. Advancements in gene therapy technologies and stem cell therapies offer promising prospects for long-lasting or permanent solutions. This review provides a comprehensive overview of OI's classification, pathogenesis, and current treatment options. It also explores emerging biotechnologies for stem cells and gene-targeted therapies in OI. The potential of these innovative therapies and their clinical implementation challenges are evaluated, focusing on their imminent success in treating bone disorders.
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Affiliation(s)
- Sachin Chaugule
- Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | | | - Aijaz Ahmad John
- Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Dimitra Micha
- Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam; Amsterdam Rare Bone Disease center, Amsterdam Bone Center, Amsterdam Movement Sciences, Amsterdam Reproduction and Development, Amsterdam, The Netherlands
| | - Marelise Eekhoff
- Department of Internal Medicine, Section Endocrinology & Metabolism, Amsterdam UMC, Vrije Universiteit Amsterdam; Amsterdam Rare Bone Disease center, Amsterdam Bone Center, Amsterdam Movement Sciences, Amsterdam Reproduction and Development Amsterdam, Amsterdam, Netherlands
| | - Ellen Gravallese
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
| | - Jae-Hyuck Shim
- Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
- Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA
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Futagawa N, Hasegawa K, Miyahara H, Tanaka H, Tsukahara H. Trabecular bone scores in children with osteogenesis imperfecta respond differently to bisphosphonate treatment depending on disease severity. Front Pediatr 2024; 12:1500023. [PMID: 39698473 PMCID: PMC11653183 DOI: 10.3389/fped.2024.1500023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 11/13/2024] [Indexed: 12/20/2024] Open
Abstract
Introduction Osteogenesis imperfecta (OI) is a congenital skeletal disorder characterized by bone fragility. Bisphosphonates (BISs) have become the mainstream treatment in children with OI. However, an optimal treatment protocol has not yet been established, while BIS treatment tends to be administered to normalize bone mineral density (BMD). Bone quality is an important component of bone strength. The trabecular bone score (TBS) is a quantitative measure of the microstructure that affects bone quality. This study investigated the TBS during BIS treatment in children with OI. Materials and methods Twenty-nine children with OI were enrolled and classified into two groups: mild (type 1) and moderate to severe (types 3 and 4). Dual-energy x-ray absorptiometry images were retrospectively analyzed for TBS calculation. The relationship between the areal BMD (aBMD), its Z-score, height-adjusted BMD (BMDHAZ) Z-score, TBS, and TBS Z-score with the treatment duration was assessed for each group. Results In the mild group, the aBMD, its Z-score, and BMDHAZ Z-score showed a significant positive correlation with treatment duration (r = 0.68, 0.68, 0.72, respectively, p < 0.01). The TBS Z-score tended to increase with treatment duration, albeit without reaching significance. In the moderate to severe group, the TBS Z-score showed a significant positive correlation with treatment duration (r = 0.48, p < 0.01), in contrast to the aBMD Z-score, which did not increase. Finally, the BMDHAZ Z-score only showed a weak positive correlation with treatment duration (r = 0.37, p < 0.01). Conclusion Because BIS affect the BMD and TBS differently based on the severity of OI, treatment goals may need to be stratified by disease severity.
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Affiliation(s)
- Natsuko Futagawa
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
- Department of Pediatrics, Okayama University Hospital, Okayama, Japan
| | - Kosei Hasegawa
- Department of Pediatrics, Okayama University Hospital, Okayama, Japan
| | - Hiroyuki Miyahara
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroyuki Tanaka
- Department of Pediatrics, Okayama Saiseikai General Hospital, Okayama, Japan
| | - Hirokazu Tsukahara
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Misof BM, Fratzl-Zelman N. Bone Quality and Mineralization and Effects of Treatment in Osteogenesis Imperfecta. Calcif Tissue Int 2024; 115:777-804. [PMID: 39231826 DOI: 10.1007/s00223-024-01263-8] [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: 03/21/2024] [Accepted: 07/10/2024] [Indexed: 09/06/2024]
Abstract
Osteogenesis imperfecta (OI) is a rare congenital bone dysplasia characterized by high fracture rates and broad variations in clinical manifestations ranging from mild to increasingly severe and perinatal lethal forms. The underlying mutations affect either the synthesis or processing of the type I procollagen molecule itself or proteins that are involved in the formation and mineralization of the collagen matrix. Consequently, the collagen forming cells, the osteoblasts, become broadly dysfunctional in OI. Strikingly, hypermineralized bone matrix seems to be a frequent feature in OI, despite the variability in clinical severity and mutations in the so far studied different forms of human OI. While the causes of the increased mineral content of the bone matrix are not fully understood yet, there is evidence that the descendants of the osteoblasts, the osteocytes, which play a critical role not only in bone remodeling, but also in mineralization and sensing of mechanical loads, are also highly dysregulated and might be of major importance in the pathogenesis of OI. In this review article, we firstly summarize findings of cellular abnormalities in osteoblasts and osteocytes, alterations of the organic matrix, as well as of the microstructural organization of bone. Secondly, we focus on the hypermineralization of the bone matrix in OI as observed in several different forms of human OI as well as in animal models, its measurement and potential mechanical implications and its effect on the bone mineral density measured by dual X-ray absorptiometry. Thirdly, we give an overview of established medication treatments of OI and new approaches with a focus of their known or possible effects on the bone material, particularly on bone matrix mineralization.
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Affiliation(s)
- Barbara M Misof
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Med. Dept. 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 Med. Dept. Hanusch Hospital, Vienna, Austria.
- Vienna Bone and Growth Center, Vienna, Austria.
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Abstract
Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal dysplasia characterized by bone fragility and deformity, growth deficiency, and other secondary connective tissue defects. OI is now understood as a collagen-related disorder caused by defects of genes whose protein products interact with collagen for folding, post-translational modification, processing and trafficking, affecting bone mineralization and osteoblast differentiation. This review provides the latest updates on genetics of OI, including new developments in both dominant and rare OI forms, as well as the signaling pathways involved in OI pathophysiology. There is a special emphasis on discoveries of recessive mutations in TENT5A, MESD, KDELR2 and CCDC134 whose causality of OI types XIX, XX, XXI and XXI, respectively, is now established and expends the complexity of mechanisms underlying OI to overlap LRP5/6 and MAPK/ERK pathways. We also review in detail new discoveries connecting the known OI types to each other, which may underlie an eventual understanding of a final common pathway in OI cellular and bone biology.
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Affiliation(s)
- Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
- Section on Adolescent Bone and Body Composition, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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Pinal-Fernandez I, Muñoz-Braceras S, Casal-Dominguez M, Pak K, Torres-Ruiz J, Musai J, Dell'Orso S, Naz F, Islam S, Gutierrez-Cruz G, Cano MD, Matas-Garcia A, Padrosa J, Tobias-Baraja E, Garrabou G, Aldecoa I, Espinosa G, Simeon-Aznar CP, Guillen-Del-Castillo A, Gil-Vila A, Trallero-Araguás E, Christopher-Stine L, Lloyd TE, Liewluck T, Naddaf E, Stenzel W, Greenberg SA, Grau JM, Selva-O'Callaghan A, Milisenda JC, Mammen AL. Pathological autoantibody internalisation in myositis. Ann Rheum Dis 2024; 83:1549-1560. [PMID: 38902010 PMCID: PMC11493519 DOI: 10.1136/ard-2024-225773] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 06/11/2024] [Indexed: 06/22/2024]
Abstract
OBJECTIVES Autoantibodies targeting intracellular proteins are common in various autoimmune diseases. In the context of myositis, the pathologic significance of these autoantibodies has been questioned due to the assumption that autoantibodies cannot enter living muscle cells. This study aims to investigate the validity of this assumption. METHODS Confocal immunofluorescence microscopy was employed to localise antibodies and other proteins of interest in myositis muscle biopsies. Bulk RNA sequencing was used to examine the transcriptomic profiles of 669 samples, including those from patients with myositis, disease controls and healthy controls. Additionally, antibodies from myositis patients were introduced into cultured myoblasts through electroporation, and their transcriptomic profiles were analysed using RNA sequencing. RESULTS In patients with myositis autoantibodies, antibodies accumulated inside myofibres in the same subcellular compartment as the autoantigen. Bulk RNA sequencing revealed that muscle biopsies from patients with autoantibodies targeting transcriptional regulators exhibited transcriptomic patterns consistent with dysfunction of the autoantigen. For instance, in muscle biopsies from patients with anti-PM/Scl autoantibodies recognising components of the nuclear RNA exosome complex, an accumulation of divergent transcripts and long non-coding RNAs was observed; these RNA forms are typically degraded by the nuclear RNA exosome complex. Introducing patient antibodies into cultured muscle cells recapitulated the transcriptomic effects observed in human disease. Further supporting evidence suggested that myositis autoantibodies recognising other autoantigens may also disrupt the function of their targets. CONCLUSIONS This study demonstrates that, in myositis, autoantibodies are internalised into living cells, causing biological effects consistent with the disrupted function of their autoantigen.
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Affiliation(s)
- Iago Pinal-Fernandez
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sandra Muñoz-Braceras
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Maria Casal-Dominguez
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Katherine Pak
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jiram Torres-Ruiz
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Jon Musai
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Stefania Dell'Orso
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Faiza Naz
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Shamima Islam
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Gustavo Gutierrez-Cruz
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Maria Dolores Cano
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
| | - Ana Matas-Garcia
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER and IDIBAPS, Barcelona, Spain
| | | | - Ester Tobias-Baraja
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER and IDIBAPS, Barcelona, Spain
| | - Gloria Garrabou
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER and IDIBAPS, Barcelona, Spain
| | - Iban Aldecoa
- Pathology, Neurological Tissue Bank, Hospital Clinic of Barcelona-CDB-IDIBAPS/FCRB-University of Barcelona, Barcelona, Spain
| | - Gerard Espinosa
- Barcelona University, Barcelona, Spain
- Department of Autoimmune Diseases, Reference Centre for Systemic Autoimmune Diseases (UEC/CSUR) of the Catalan and Spanish Health Systems-Member of ERN-ReCONNET, Hospital Clinic, Barcelona, Spain
| | - Carmen Pilar Simeon-Aznar
- Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | - Alfredo Guillen-Del-Castillo
- Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | - Albert Gil-Vila
- Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | - Ernesto Trallero-Araguás
- Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
- Rheumatology Department, Vall d'Hebron Hospital, Barcelona, Spain
| | - Lisa Christopher-Stine
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Thomas E Lloyd
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Teerin Liewluck
- Division of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
| | - Elie Naddaf
- Division of Neuromuscular Medicine, Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
| | - Werner Stenzel
- Department of Neuropathology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Steven A Greenberg
- Department of Neurology, Brigham and Women's Hospital and Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Josep Maria Grau
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER and IDIBAPS, Barcelona, Spain
| | - Albert Selva-O'Callaghan
- Systemic Autoimmune Disease Section, Vall d'Hebron Institute of Research, Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | - Jose Cesar Milisenda
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER and IDIBAPS, Barcelona, Spain
| | - Andrew Lee Mammen
- Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Muthusamy M, Nagarajan M, Karuppusamy S, Ramasamy KT, Ramasamy A, Kalaivanan R, Thippicettipalayam Ramasamy GKM, Aranganoor Kannan T. "Unveiling the genetic symphony: Diversity and expression of chicken IFITM genes in Aseel and Kadaknath breeds". Heliyon 2024; 10:e37729. [PMID: 39315180 PMCID: PMC11417226 DOI: 10.1016/j.heliyon.2024.e37729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 09/04/2024] [Accepted: 09/09/2024] [Indexed: 09/25/2024] Open
Abstract
In this investigation, single nucleotide variants (SNVs) within the chicken interferon-inducible transmembrane protein (chIFITM) genes were explored in Aseel and Kadaknath breeds. Comparative analysis with the GRCg6a reference genome revealed 9 and 16 SNVs in the chIFITM locus for Aseel and Kadaknath breeds, respectively. When referencing the Genome Reference Consortium GRCg7b, Kadaknath exhibited 10 variants, contrasting with none in Aseel. Notably, 17, 8, 2, and 5 SNVs were identified in chIFITM1, chIFITM2, chIFITM3, and chIFITM5 genes, with chIFITM1 showing the highest polymorphism in Kadaknath, featuring 10 intronic variants, including three SNVs (rs16457112, rs16457111, and rs313341707) common to both breeds. Two synonymous exonic variants (g.1817767C > A and g.1819102C > T) were also noted in chIFITM1. Although chIFITM protein sequences were generally conserved, genetic variations clustered predominantly in UTR and intronic regions. Examination of immune response dynamics in live embryos uncovered notable variations in chIFITM gene expression across diverse organs and chicken breeds. Specifically, chIFITM1 mRNA was abundant in cecal tonsils for both breeds and bursa of Aseel (7.61 folds), but it was absent in the heart and lung tissues of both breeds. Conversely, chIFITM3 consistently exhibited heightened expression, particularly in bursa of Aseel (10.23 folds). Whereas mRNA of the chIFITM2 gene was found to be abundant in the heart of Kadaknath (11.03 folds) and lung of both breeds. Furthermore, the expression pattern of chIFITM5 diverged between the two breeds, the heart of Kadaknath chickens showed highest (10.45 folds). The study discovered that breed-specific genetic variants within these genes present a potential pathway for selection and breeding to improve disease resistance in chicken. The observed genetic variation among chicken populations highlights the critical importance of these variants in reinforcing virus resistance, exhibiting applicability across a wide range of breeds.
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Affiliation(s)
- Malarmathi Muthusamy
- Veterinary College and Research Institute, Tamil Nadu Veterinary and Animal Sciences University, Namakkal, 637 002, India
| | - Murali Nagarajan
- Alambadi Cattle Breed Research Centre, Tamil Nadu Veterinary and Animal Sciences University, Dharmapuri, 635 111, India
| | - Sivakumar Karuppusamy
- Faculty of Food and Agriculture, The University of the West Indies, St Augustine, Trinidad and Tobago
| | | | - Amutha Ramasamy
- Veterinary College and Research Institute, Tamil Nadu Veterinary and Animal Sciences University, Namakkal, 637 002, India
| | - Ramya Kalaivanan
- Veterinary College and Research Institute, Tamil Nadu Veterinary and Animal Sciences University, Namakkal, 637 002, India
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9
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Deuis JR, Klasfauseweh T, Walker L, Vetter I. The 'dispanins' and related proteins in physiology and neurological disease. Trends Neurosci 2024; 47:622-634. [PMID: 39025729 DOI: 10.1016/j.tins.2024.06.004] [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: 02/21/2024] [Revised: 05/15/2024] [Accepted: 06/21/2024] [Indexed: 07/20/2024]
Abstract
The dispanins are a family of 15 transmembrane proteins that have diverse and often unclear physiological functions. Many dispanins, including synapse differentiation induced gene 1 (SynDIG1), proline-rich transmembrane protein 1 (PRRT1)/SynDIG4, and PRRT2, are expressed in the central nervous system (CNS), where they are involved in the development of synapses, regulation of neurotransmitter release, and interactions with ion channels, including AMPA receptors (AMPARs). Others, including transmembrane protein 233 (TMEM233) and trafficking regulator of GLUT4-1 (TRARG1), are expressed in the peripheral nervous system (PNS); however, the function of these dispanins is less clear. Recently, a family of neurotoxins isolated from the giant Australian stinging tree was shown to target TMEM233 to modulate the function of voltage-gated sodium (NaV) channels, suggesting that the dispanins are inherently druggable. Here, we review current knowledge about the structure and function of the dispanins, in particular TMEM233 and its two most closely related homologs PRRT2 and TRARG1, which may be drug targets involved in neurological disease.
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Affiliation(s)
- Jennifer R Deuis
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Tabea Klasfauseweh
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Lucinda Walker
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Irina Vetter
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia.
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10
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Marom R, Song IW, Busse EC, Washington ME, Berrier AS, Rossi VC, Ortinau L, Jeong Y, Jiang MM, Dawson BC, Adeyeye M, Leynes C, Lietman CD, Stroup BM, Batkovskyte D, Jain M, Chen Y, Cela R, Castellon A, Tran AA, Lorenzo I, Meyers DN, Huang S, Turner A, Shenava V, Wallace M, Orwoll E, Park D, Ambrose CG, Nagamani SC, Heaney JD, Lee BH. The IFITM5 mutation in osteogenesis imperfecta type V is associated with an ERK/SOX9-dependent osteoprogenitor differentiation defect. J Clin Invest 2024; 134:e170369. [PMID: 38885336 PMCID: PMC11290974 DOI: 10.1172/jci170369] [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: 03/08/2023] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Osteogenesis imperfecta (OI) type V is the second most common form of OI, distinguished by hyperplastic callus formation and calcification of the interosseous membranes, in addition to the bone fragility. It is caused by a recurrent, dominant pathogenic variant (c.-14C>T) in interferon-induced transmembrane protein 5 (IFITM5). Here, we generated a conditional Rosa26-knockin mouse model to study the mechanistic consequences of the recurrent mutation. Expression of the mutant Ifitm5 in osteo-chondroprogenitor or chondrogenic cells resulted in low bone mass and growth retardation. Mutant limbs showed impaired endochondral ossification, cartilage overgrowth, and abnormal growth plate architecture. The cartilage phenotype correlates with the pathology reported in patients with OI type V. Surprisingly, expression of mutant Ifitm5 in mature osteoblasts caused no obvious skeletal abnormalities. In contrast, earlier expression in osteo-chondroprogenitors was associated with an increase in the skeletal progenitor cell population within the periosteum. Lineage tracing showed that chondrogenic cells expressing the mutant Ifitm5 had decreased differentiation into osteoblastic cells in diaphyseal bone. Moreover, mutant IFITM5 disrupted early skeletal homeostasis in part by activating ERK signaling and downstream SOX9 protein, and inhibition of these pathways partially rescued the phenotype in mutant animals. These data identify the contribution of a signaling defect altering osteo-chondroprogenitor differentiation as a driver in the pathogenesis of OI type V.
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Affiliation(s)
- Ronit Marom
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Hospital, Houston, Texas, USA
| | - I-Wen Song
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Emily C. Busse
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA
| | - Megan E. Washington
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Ava S. Berrier
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Vittoria C. Rossi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Hospital, Houston, Texas, USA
| | - Laura Ortinau
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Youngjae Jeong
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Ming-Ming Jiang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Brian C. Dawson
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Mary Adeyeye
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Medical Scientist Training Program, UT Health Houston MD Anderson Cancer Center, Houston, Texas, USA
| | - Carolina Leynes
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Caressa D. Lietman
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Bridget M. Stroup
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Dominyka Batkovskyte
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Mahim Jain
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Yuqing Chen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Racel Cela
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Alexis Castellon
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Alyssa A. Tran
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Isabel Lorenzo
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - D. Nicole Meyers
- Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, Texas, USA
| | - Shixia Huang
- Department of Molecular and Cellular Biology, and Huffington Department of Education, Innovation, and Technology, Advanced Technology Cores, and
| | - Alicia Turner
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Hospital, Houston, Texas, USA
| | - Vinitha Shenava
- Department of Orthopedic Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Maegen Wallace
- Orthopaedic Surgery, University of Nebraska Medical Center, Children’s Hospital and Medical Center, Omaha, Nebraska, USA
| | - Eric Orwoll
- Department of Medicine, Bone and Mineral Unit, Oregon Health and Science University, Portland, Oregon, USA
| | - Dongsu Park
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Catherine G. Ambrose
- Department of Orthopaedic Surgery, McGovern Medical School at UT Health, Houston, Texas, USA
| | - Sandesh C.S. Nagamani
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Hospital, Houston, Texas, USA
| | - Jason D. Heaney
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Brendan H. Lee
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Texas Children’s Hospital, Houston, Texas, USA
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11
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Martínez-Montoya V, Fonseca-Sánchez MA, Fabian-Morales G, Vega-Gamas R, Queipo-García GE, León-Madero LF, Sánchez-Sánchez LM. IFITM5-related (type V) osteogenesis imperfecta with evidence of perinatal involvement: A case report. Bone Rep 2024; 21:101766. [PMID: 38681748 PMCID: PMC11052912 DOI: 10.1016/j.bonr.2024.101766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 05/01/2024] Open
Abstract
Osteogenesis imperfecta (OI) is a rare hereditary disorder characterized by bone fragility and frequent fractures. While most cases are attributed to variations in collagen-coding genes COL1A1 and COL1A2, other genes such as IFITM5 have also been associated with the disease, accounting for up to 5 % of cases. Here, we report a case of a 3-month-old female with a femur fracture and limb deformity. X-rays revealed evidence of osteopenia and previous fractures in the arms, clavicle, ribs, and left limb, alongside prenatal bone deformities detected by ultrasound. Initial clinical evaluation suggested progressively deforming (Sillence's type III) osteogenesis imperfecta (OI). Molecular testing led to the diagnosis of IFITM5-related OI, identifying the c.-14C>T (rs587776916) variant. Although this variant has been previously reported in patients with IFITM5-related OI, prenatal involvement had not been associated with this variant.
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Affiliation(s)
- Valentina Martínez-Montoya
- Medical Genetics Service, NanoLab Next Generation Diagnostics, Mexico City, Mexico
- Genetics Service, Instituto Médico de la Visión, Mexico City, Mexico
| | | | | | - Ramiro Vega-Gamas
- Medical Genetics Service, NanoLab Next Generation Diagnostics, Mexico City, Mexico
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12
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Yung D, Arai M, Matsumoto S, Sato T, Hirozane T, Yamaguchi S, Asano N, Hasegawa T, Nakayama R. Sequential imaging of hyperplastic callus formation in Osteogenesis Imperfecta type V: A case report and review of the literature. J Orthop Sci 2023; 28:1430-1435. [PMID: 34090776 DOI: 10.1016/j.jos.2021.04.009] [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: 03/01/2021] [Revised: 03/31/2021] [Accepted: 04/06/2021] [Indexed: 11/21/2022]
Affiliation(s)
- David Yung
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
| | - Manabu Arai
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan.
| | - Shunsuke Matsumoto
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan.
| | - Takeshi Sato
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
| | - Toru Hirozane
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
| | - Sayaka Yamaguchi
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
| | - Naofumi Asano
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
| | - Tomonobu Hasegawa
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
| | - Robert Nakayama
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.
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13
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Marziali F, Song Y, Nguyen XN, Belmudes L, Burlaud-Gaillard J, Roingeard P, Couté Y, Cimarelli A. A Proteomics-Based Approach Identifies the NEDD4 Adaptor NDFIP2 as an Important Regulator of Ifitm3 Levels. Viruses 2023; 15:1993. [PMID: 37896772 PMCID: PMC10611234 DOI: 10.3390/v15101993] [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: 08/25/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 10/29/2023] Open
Abstract
IFITMs are a family of highly related interferon-induced transmembrane proteins that interfere with the processes of fusion between viral and cellular membranes and are thus endowed with broad antiviral properties. A number of studies have shown how the antiviral potency of IFITMs is highly dependent on their steady-state levels, their intracellular distribution and a complex pattern of post-translational modifications, parameters that are overall tributary of a number of cellular partners. In an effort to identify additional protein partners involved in the biology of IFITMs, we devised a proteomics-based approach based on the piggyback incorporation of IFITM3 partners into extracellular vesicles. MS analysis of the proteome of vesicles bearing or not bearing IFITM3 identified the NDFIP2 protein adaptor protein as an important regulator of IFITM3 levels. NDFIP2 is a membrane-anchored adaptor protein of the E3 ubiquitin ligases of the NEDD4 family that have already been found to be involved in IFITM3 regulation. We show here that NDFIP2 acts as a recruitment factor for both IFITM3 and NEDD4 and mediates their distribution in lysosomal vesicles. The genetic inactivation and overexpression of NDFIP2 drive, respectively, lower and higher levels of IFITM3 accumulation in the cell, overall suggesting that NDFIP2 locally competes with IFITM3 for NEDD4 binding. Given that NDFIP2 is itself tightly regulated and highly responsive to external cues, our study sheds light on a novel and likely dynamic layer of regulation of IFITM3.
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Affiliation(s)
- Federico Marziali
- Centre International de Recherche en Infectiologie (CIRI), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69100 Lyon, France (X.-N.N.)
| | - Yuxin Song
- Centre International de Recherche en Infectiologie (CIRI), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69100 Lyon, France (X.-N.N.)
| | - Xuan-Nhi Nguyen
- Centre International de Recherche en Infectiologie (CIRI), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69100 Lyon, France (X.-N.N.)
| | - Lucid Belmudes
- Université Grenoble Alpes, INSERM, CEA, UA13 BGE, CNRS, CEA, 38000 Grenoble, France; (L.B.); (Y.C.)
| | - Julien Burlaud-Gaillard
- Plateforme IBiSA de Microscopie Electronique, Université de Tours et CHU de Tours, 37000 Tours, France; (J.B.-G.); (P.R.)
| | - Philippe Roingeard
- Plateforme IBiSA de Microscopie Electronique, Université de Tours et CHU de Tours, 37000 Tours, France; (J.B.-G.); (P.R.)
- INSERM U1259, Université de Tours et CHU de Tours, 37000 Tours, France
| | - Yohann Couté
- Université Grenoble Alpes, INSERM, CEA, UA13 BGE, CNRS, CEA, 38000 Grenoble, France; (L.B.); (Y.C.)
| | - Andrea Cimarelli
- Centre International de Recherche en Infectiologie (CIRI), Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69100 Lyon, France (X.-N.N.)
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14
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Chen P, Zhou Y, Tan Z, Lin Y, Lin DLL, Wu J, Li Z, Shek HT, Wu J, Hu Y, Zhu F, Chan D, Cheung KMC, To MKT. Scoliosis in osteogenesis imperfecta: identifying the genetic and non-genetic factors affecting severity and progression from longitudinal data of 290 patients. Orphanet J Rare Dis 2023; 18:295. [PMID: 37730650 PMCID: PMC10510243 DOI: 10.1186/s13023-023-02906-z] [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: 04/14/2023] [Accepted: 09/04/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Scoliosis is widely prevalent among osteogenesis imperfecta (OI) patients, and is progressive with age. However, factors affecting scoliosis in OI are not well known. METHODS We retrospectively retrieved longitudinal radiographic and clinical records of consecutive OI patients seeking treatments at our hospital from 2014 to 2022, graded their pre-operative spinal conditions into four outcome groups, estimated their progression rates, and descriptively and inferentially analyzed the genetic and non-genetic factors that may affect the outcomes and progression rates. RESULTS In all, 290 OI patients met the inclusion criteria, where 221 had genetic records. Of these 221, about 2/3 had mutations in COL1A1 or COL1A2, followed by mutations in WNT1 (9.0%), IFITM5 (9.0%) and other OI risk genes. With an average age of 12.0 years (interquartile range [IQR] 6.9-16.1), 70.7% of the cohort had scoliosis (Cobb angle > 10°), including 106 (36.5%) mild (10°-25°), 40 (13.8%) moderate (25°-50°), and 59 (20.3%) severe (> 50°) scoliosis patients. Patients with either COL1A1 and COL1A2 were strongly biased toward having mild or no scoliosis, whereas patients with mutations in IFITM5, WNT1 and other recessive genes were more evenly distributed among the four outcome grades. Lower-limb discrepancy, bone mineral density (BMD) and age of first drug used were all significantly correlated with severity outcomes. Using multivariate logistic regression, we estimated that each year older adds an odds ratio of 1.13 (95% confidence interval [CI] 1.07-1.2) in progression into advanced stages of scoliosis. We estimated a cohort-wide progression rate of 2.7 degrees per year (95% CI 2.4-3.0). Early-onset patients experienced fast progressions during both infantile and adolescent stages. Twenty-five of the 59 (42.8%) patients with severe scoliosis underwent spinal surgeries, enjoying an average Cobb angle reduction of 33° (IQR 23-40) postoperatively. CONCLUSION The severity and progression of scoliosis in osteogenesis imperfecta were affected by genetic factors including genotypes and mutation types, and non-genetic factors including age and BMD. As compared with COL1A1, mutations in COL1A2 were less damaging while those on IFITM5 and other recessive genes conferred damaging effects. Progression rates were the fastest in the adolescent adult age-group.
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Affiliation(s)
- Peikai Chen
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China.
- School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong.
- The Artificial Intelligence and Big Data (AIBD) Lab, The University of Hong Kong - Shenzhen Hospital, Shenzhen, 518053, Guangdong, China.
| | - Yapeng Zhou
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
| | - Zhijia Tan
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
- Department of Orthopedics and Traumatology, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Yunzhi Lin
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
| | - Daniel Li-Liang Lin
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
| | - Jingwei Wu
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
| | - Zeluan Li
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
| | - Hiu Tung Shek
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
| | - Jianbin Wu
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
| | - Yong Hu
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
- Department of Orthopedics and Traumatology, The University of Hong Kong, Pok Fu Lam, Hong Kong
- The Artificial Intelligence and Big Data (AIBD) Lab, The University of Hong Kong - Shenzhen Hospital, Shenzhen, 518053, Guangdong, China
| | - Feng Zhu
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
- Department of Orthopedics and Traumatology, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Danny Chan
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
- School of Biomedical Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Kenneth Man-Chee Cheung
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China
- Department of Orthopedics and Traumatology, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Michael Kai-Tsun To
- Department of Orthopedics and Traumatology, The University of Hong Kong - Shenzhen Hospital (HKU-SZH), Shenzhen, 518053, Guangdong, China.
- Department of Orthopedics and Traumatology, The University of Hong Kong, Pok Fu Lam, Hong Kong.
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15
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Pinal-Fernandez I, Milisenda JC, Pak K, Muñoz-Braceras S, Casal-Dominguez M, Torres-Ruiz J, Dell'Orso S, Naz F, Gutierrez-Cruz G, Duque-Jaimez Y, Matas-Garcia A, Padrosa J, Garcia-Garcia FJ, Guitart-Mampel M, Garrabou G, Trallero-Araguás E, Walitt B, Paik JJ, Albayda J, Christopher-Stine L, Lloyd TE, Grau-Junyent JM, Selva-O'Callaghan A, Mammen AL. Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies. Ann Rheum Dis 2023; 82:1091-1097. [PMID: 37130727 PMCID: PMC11611052 DOI: 10.1136/ard-2023-223873] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/18/2023] [Indexed: 05/04/2023]
Abstract
OBJECTIVES Myositis is a heterogeneous family of diseases including dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), antisynthetase syndrome (AS) and inclusion body myositis (IBM). Myositis-specific autoantibodies define different subtypes of myositis. For example, patients with anti-Mi2 autoantibodies targeting the chromodomain helicase DNA-binding protein 4 (CHD4)/NuRD complex (a transcriptional repressor) have more severe muscle disease than other DM patients. This study aimed to define the transcriptional profile of muscle biopsies from anti-Mi2-positive DM patients. METHODS RNA sequencing was performed on muscle biopsies (n=171) from patients with anti-Mi2-positive DM (n=18), DM without anti-Mi2 autoantibodies (n=32), AS (n=18), IMNM (n=54) and IBM (n=16) as well as 33 normal muscle biopsies. Genes specifically upregulated in anti-Mi2-positive DM were identified. Muscle biopsies were stained for human immunoglobulin and protein products corresponding to genes specifically upregulated in anti-Mi2-positive muscle biopsies. RESULTS A set of 135 genes, including SCRT1 and MADCAM1, was specifically overexpressed in anti-Mi2-positive DM muscle. This set was enriched for CHD4/NuRD-regulated genes and included genes that are not otherwise expressed in skeletal muscle. The expression levels of these genes correlated with anti-Mi2 autoantibody titres, markers of disease activity and with the other members of the gene set. In anti-Mi2-positive muscle biopsies, immunoglobulin was localised to the myonuclei, MAdCAM-1 protein was present in the cytoplasm of perifascicular fibres, and SCRT1 protein was localised to myofibre nuclei. CONCLUSIONS Based on these findings, we hypothesise that anti-Mi2 autoantibodies could exert a pathogenic effect by entering damaged myofibres, inhibiting the CHD4/NuRD complex, and subsequently derepressing the unique set of genes defined in this study.
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Affiliation(s)
- Iago Pinal-Fernandez
- Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jose Cesar Milisenda
- Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER, Barcelona, Spain
| | - Katherine Pak
- Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Sandra Muñoz-Braceras
- Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Maria Casal-Dominguez
- Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jiram Torres-Ruiz
- Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Stefania Dell'Orso
- Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Faiza Naz
- Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Gustavo Gutierrez-Cruz
- Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Yaiza Duque-Jaimez
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
| | - Ana Matas-Garcia
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER, Barcelona, Spain
| | | | - Francesc J Garcia-Garcia
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER, Barcelona, Spain
| | - Mariona Guitart-Mampel
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER, Barcelona, Spain
| | - Gloria Garrabou
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER, Barcelona, Spain
| | | | - Brian Walitt
- National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland, USA
| | - Julie J Paik
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jemima Albayda
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lisa Christopher-Stine
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Thomas E Lloyd
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Josep Maria Grau-Junyent
- Muscle Research Unit, Internal Medicine Service, Hospital Clinic, Barcelona, Spain
- Barcelona University, Barcelona, Spain
- CIBERER, Barcelona, Spain
| | - Albert Selva-O'Callaghan
- Systemic Autoimmune Disease Unit, Vall d'Hebron Institute of Research, Barcelona, Spain
- Autonomous University of Barcelona, Barcelona, Spain
| | - Andrew Lee Mammen
- Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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16
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Kumar A, Saikia UK, Bhuyan AK, Baro A, Prasad SG. Zoledronic Acid Treatment in Infants and Toddlers with Osteogenesis Imperfecta is Safe and Effective: A Tertiary Care Centre Experience. Indian J Endocrinol Metab 2023; 27:255-259. [PMID: 37583407 PMCID: PMC10424114 DOI: 10.4103/ijem.ijem_268_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/30/2022] [Accepted: 10/29/2022] [Indexed: 08/17/2023] Open
Abstract
Context Osteogenesis imperfecta (OI) is a genetic disorder of the extracellular matrix of bone characterized by low bone mass manifesting as frequent fractures, delayed motor development, pain, and impaired quality of life. The intravenous bisphosphonate, pamidronate is an established treatment for OI. Recently, zoledronic acid (ZA) has been used for the management of OI. Aim To assess the efficacy and safety of ZA in children below five years of age with OI. Settings and Design A hospital-based prospective observational study. Methods and Material Patients with OI aged less than five years attending our centre were treated with intravenous ZA at a dose of 0.05 mg/kg every six months. Subjects were closely monitored for clinical and biochemical variables, adverse events, and new-onset fractures. The response to therapy was assessed by monitoring clinical variables including the degree of bony pains, number of fractures, height/length standard deviation score (SDS), and motor developmental milestones. All patients were analysed at baseline and at the end of two years for biochemical parameters and clinical severity score (CSS) as proposed by Aglan et al. with modifications. Results After two years of treatment, OI patients showed a significant decline in the rate of fractures (p < 0.001), improvement in ambulation (p = 0.005), alleviation of pain (p < 0.001), and improvement in height SDS (p < 0.05). There was a significant improvement in CSS after two years of therapy. Apart from mild flu-like symptoms and mild asymptomatic hypocalcaemia immediately post-infusion, no other adverse effect was noted. Conclusion ZA therapy in infants and children below five years of age with OI was effective and safe and a more convenient alternative to pamidronate.
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Affiliation(s)
- Angad Kumar
- Department of Endocrinology, Gauhati Medical College and Hospital, Guwahati, Assam, India
| | - Uma K. Saikia
- Department of Endocrinology, Gauhati Medical College and Hospital, Guwahati, Assam, India
| | - Ashok K. Bhuyan
- Department of Endocrinology, Gauhati Medical College and Hospital, Guwahati, Assam, India
| | - Abhamoni Baro
- Department of Endocrinology, Gauhati Medical College and Hospital, Guwahati, Assam, India
| | - Surendra G. Prasad
- Department of Endocrinology, Gauhati Medical College and Hospital, Guwahati, Assam, India
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17
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Handa A, Grigelioniene G, Nishimura G. Skeletal Dysplasia Families: A Stepwise Approach to Diagnosis. Radiographics 2023; 43:e220067. [PMID: 37053103 DOI: 10.1148/rg.220067] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
Skeletal dysplasias are a heterogeneous collection of genetic disorders characterized by bone and cartilage abnormalities, and they encompass over 400 disorders. These disorders are rare individually, but collectively they are common (approximate incidence of one in 5000 births). Radiologists occasionally encounter skeletal dysplasias in daily practice. In the 1980s, Professor Juergen Spranger proposed a concept suitable for the diagnosis of skeletal dysplasias termed bone dysplasia families. He stated that (a) different bone dysplasias that share a similar skeletal pattern can be grouped into a "family," (b) the final diagnosis is feasible through the provisional recognition of a pattern followed by a more careful analysis, and (c) families of bone dysplasias may be the result of similar pathogenetic mechanisms. The prototypes of bone dysplasia families include dysostosis multiplex family, achondroplasia family, spondyloepiphyseal dysplasia congenita family, and Larsen syndrome-otopalatodigital syndrome family. Since Spranger's proposal, the concept of bone dysplasia families, along with advancing genetic techniques, has been validated and further expanded. Today, this molecularly proven concept enables a simple stepwise approach to be applied to the radiologic diagnosis of skeletal dysplasias. The first step is the categorization of a given case into a family based on pattern recognition, and the second step is more meticulous observation, such as identification of different severities of the same pattern or subtle but distinctive findings. Since major skeletal dysplasias are limited in number, radiologists can be familiar with the representative patterns of these disorders. The authors describe a stepwise radiologic approach to diagnosing major skeletal dysplasia families and review the clinical and genetic features of these disorders. Published under a CC BY 4.0 license. Quiz questions for this article are available through the Online Learning Center. Online supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article.
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Affiliation(s)
- Atsuhiko Handa
- From the Department of Radiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115 (A.H.); Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (G.G., G.N.); Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden (G.G.); Department of Clinical Genetics and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden (G.G.); and Center for Intractable Diseases, Saitama University Hospital, Saitama, Japan (G.N.)
| | - Giedre Grigelioniene
- From the Department of Radiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115 (A.H.); Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (G.G., G.N.); Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden (G.G.); Department of Clinical Genetics and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden (G.G.); and Center for Intractable Diseases, Saitama University Hospital, Saitama, Japan (G.N.)
| | - Gen Nishimura
- From the Department of Radiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115 (A.H.); Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (G.G., G.N.); Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden (G.G.); Department of Clinical Genetics and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden (G.G.); and Center for Intractable Diseases, Saitama University Hospital, Saitama, Japan (G.N.)
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18
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Panzaru MC, Florea A, Caba L, Gorduza EV. Classification of osteogenesis imperfecta: Importance for prophylaxis and genetic counseling. World J Clin Cases 2023; 11:2604-2620. [PMID: 37214584 PMCID: PMC10198117 DOI: 10.12998/wjcc.v11.i12.2604] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/18/2023] [Accepted: 03/27/2023] [Indexed: 04/25/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a genetically heterogeneous monogenic disease characterized by decreased bone mass, bone fragility, and recurrent fractures. The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature. The basic mechanism is a collagen-related defect, not only in synthesis but also in folding, processing, bone mineralization, or osteoblast function. In recent years, great progress has been made in identifying new genes and molecular mechanisms underlying OI. In this context, the classification of OI has been revised several times and different types are used. The Sillence classification, based on clinical and radiological characteristics, is currently used as a grading of clinical severity. Based on the metabolic pathway, the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches. Genetic classification has the advantage of identifying the inheritance pattern, an essential element for genetic counseling and prophylaxis. Although genotype-phenotype correlations may sometimes be challenging, genetic diagnosis allows a personalized management strategy, accurate family planning, and pregnancy management decisions including options for mode of delivery, or early antenatal OI treatment. Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches. This narrative review summarizes our current understanding of genes, molecular mechanisms involved in OI, classifications, and their utility in prophylaxis.
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Affiliation(s)
- Monica-Cristina Panzaru
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Andreea Florea
- Department of Medical Genetics - Medical Genetics resident, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Lavinia Caba
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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19
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Jeong SH, Nguyen KT, Nguyen MT, You JS, Kim BH, Choe HC, Ahn SG. DMP1 and IFITM5 Regulate Osteogenic Differentiation of MC3T3-E1 on PEO-Treated Ti-6Al-4V-Ca 2+/P i surface. ACS Biomater Sci Eng 2023; 9:1377-1390. [PMID: 36802481 DOI: 10.1021/acsbiomaterials.2c01296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Despite numerous studies on various surface modifications on titanium and its alloys, it remains unclear what kind of titanium-based surface modifications are capable of controlling cell activity. This study aimed to understand the mechanism at the cellular and molecular levels and investigate the in vitro response of osteoblastic MC3T3-E1 cultured on the Ti-6Al-4V surface modified by plasma electrolytic oxidation (PEO) treatment. A Ti-6Al-4V surface was prepared by PEO at 180, 280, and 380 V for 3 or 10 min in an electrolyte containing Ca2+/Pi ions. Our results showed that PEO-treated Ti-6Al-4V-Ca2+/Pi surfaces enhanced the cell attachment and differentiation of MC3T3-E1 compared to the untreated Ti-6Al-4V control but did not affect cytotoxicity as shown by cell proliferation and cell death. Interestingly, on the Ti-6Al-4V-Ca2+/Pi surface treated by PEO at 280 V for 3 or 10 min, MC3T3-E1 showed a higher initial adhesion and mineralization. In addition, the alkaline phosphatase (ALP) activity significantly increased in MC3T3-E1 on the PEO-treated Ti-6Al-4V-Ca2+/Pi (280 V for 3 or 10 min). In RNA-seq analysis, the expression of dentin matrix protein 1 (DMP1), sortilin 1 (Sort1), signal-induced proliferation-associated 1 like 2 (SIPA1L2), and interferon-induced transmembrane protein 5 (IFITM5) was induced during the osteogenic differentiation of MC3T3-E1 on the PEO-treated Ti-6Al-4V-Ca2+/Pi. DMP1 and IFITM5 silencing decreased the expression of bone differentiation-related mRNAs and proteins and ALP activity in MC3T3-E1. These results suggest that the PEO-treated Ti-6Al-4V-Ca2+/Pi surface induces osteoblast differentiation by regulating the expression of DMP1 and IFITM5. Therefore, surface microstructure modification through PEO coatings with Ca2+/Pi ions could be used as a valuable method to improve biocompatibility properties of titanium alloys.
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Affiliation(s)
- Se-Ho Jeong
- Department of Pathology, School of Dentistry, Chosun University, Gwangju 61452, Republic of Korea
| | - Khanh Toan Nguyen
- Department of Pathology, School of Dentistry, Chosun University, Gwangju 61452, Republic of Korea
| | - Manh Tuong Nguyen
- Department of Pathology, School of Dentistry, Chosun University, Gwangju 61452, Republic of Korea
| | - Jae-Seek You
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Chosun University, Gwangju 61452, Republic of Korea
| | - Byung-Hoon Kim
- Advanced Functional Surface and Biomaterials Research Lab, Department of Dental Materials and Research Center of Surface Control for Oral Tissue Regeneration (BRL Center of NRF), College of Dentistry, Chosun University, Gwangju 61452, Republic of Korea
| | - Han-Cheol Choe
- Advanced Functional Surface and Biomaterials Research Lab, Department of Dental Materials and Research Center of Surface Control for Oral Tissue Regeneration (BRL Center of NRF), College of Dentistry, Chosun University, Gwangju 61452, Republic of Korea
| | - Sang-Gun Ahn
- Department of Pathology, School of Dentistry, Chosun University, Gwangju 61452, Republic of Korea
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20
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Tan Z, Shek HT, Dong Z, Feng L, Zhou Y, Yin S, Qiu A, Dong L, Gao B, Chen P, To MKT. Retrospective analyses of clinical features in 28 Chinese patients with type V osteogenesis imperfecta: new perspectives in an old issue. Osteoporos Int 2023; 34:369-377. [PMID: 36456709 PMCID: PMC9852172 DOI: 10.1007/s00198-022-06581-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/19/2022] [Indexed: 12/04/2022]
Abstract
UNLABELLED Type V osteogenesis imperfecta (OI) is a form of OI characterized by radial head dislocation (RHD), calcification of interosseous membrane (CIM), and hyperplastic callus (HPC). In this study, we characterized the clinical features of 28 type V OI patients. We presented that dysfunctions of elbow, hip joint, and abnormal epiphyseal growth plate were associated with ectopic calcification and summarized the history of HPC progression and treatment. INTRODUCTION The current study aims to systematically characterize the skeletal phenotypes of patients with type V OI and suggested possible surgical solutions. METHODS A total of 28 patients were admitted for inpatient care at The Hong Kong University-Shenzhen Hospital diagnosed with type V OI (either clinically diagnosed or genetically confirmed with the IFITM5 c.-14C > T mutation). RESULTS Prevalence of type V radiological features was comparable to previous literatures (RHD, 100%; CIM, 100%; HPC, 44%; and scoliosis, 50%). Novel skeletal phenotypes were presented including extension of coronoid process, acetabular labrum, acetabular protrusion, spontaneous autofusion of the hip, bulbous epiphysis, and popcorn calcification. Significant increase in BMD was observed in patients with bisphosphonate treatment. Twenty-five percent (3/12) of patients with preoperative use of indomethacin developed HPC postoperatively, and HPCs were absorbed in 2 young patients 2 years later. CONCLUSION This retrospective study summarized the clinical features and highlighted the abnormalities in elbow, hip joint, and growth plate in type V OI patients. Our study contributed to a more comprehensive clinical spectrum of type V OI. We also characterized the natural progression of HPC formation and resorption in patients in different ages. The use of bisphosphonate treatment is effective in improving bone mineral density in type V OI patients, and whether indomethacin can reduce incidence of HPC formation deserves further investigation.
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Affiliation(s)
- Zhijia Tan
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hiu Tung Shek
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Zhongxin Dong
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Lin Feng
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Yapeng Zhou
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Shijie Yin
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Anmei Qiu
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Lina Dong
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Bo Gao
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Peikai Chen
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
| | - Michael Kai Tsun To
- Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
- Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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21
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Ghosh DK, Udupa P, Shrikondawar AN, Bhavani GS, Shah H, Ranjan A, Girisha KM. Mutant MESD links cellular stress to type I collagen aggregation in osteogenesis imperfecta type XX. Matrix Biol 2023; 115:81-106. [PMID: 36526215 PMCID: PMC7615836 DOI: 10.1016/j.matbio.2022.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/19/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022]
Abstract
Aberrant forms of endoplasmic reticulum (ER)-resident chaperones are implicated in loss of protein quality control in rare diseases. Here we report a novel mutation (p.Asp233Asn) in the ER retention signal of MESD by whole exome sequencing of an individual diagnosed with osteogenesis imperfecta (OI) type XX. While MESDD233N has similar stability and chaperone activity as wild-type MESD, its mislocalization to cytoplasm leads to imbalance of ER proteostasis, resulting in improper folding and aggregation of proteins, including LRP5 and type I collagen. Aggregated LRP5 loses its plasma membrane localization to disrupt the expression of WNT-responsive genes, such as BMP2, BMP4, in proband fibroblasts. We show that MESD is a direct chaperone of pro-α1(I) [COL1A1], and absence of MESDD233N in ER results in cytosolic type I collagen aggregates that remain mostly not secreted. While cytosolic type I collagen aggregates block the intercellular nanotubes, decreased extracellular type I collagen also results in loss of interaction of ITGB1 with type I collagen and weaker attachment of fibroblasts to matrix. Although proband fibroblasts show increased autophagy to degrade the aggregated type I collagen, an overall cellular stress overwhelms the proband fibroblasts. In summary, we present an essential chaperone function of MESD for LRP5 and type I collagen and demonstrating how the D233N mutation in MESD correlates with impaired WNT signaling and proteostasis in OI.
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Affiliation(s)
- Debasish Kumar Ghosh
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
| | - Prajna Udupa
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Akshaykumar Nanaji Shrikondawar
- Computational and Functional Genomics Group, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, Telangana, India
| | - Gandham SriLakshmi Bhavani
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Hitesh Shah
- Department of Pediatric Orthopedics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Akash Ranjan
- Computational and Functional Genomics Group, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, Telangana, India
| | - Katta M Girisha
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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22
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Pachajoa H, Giraldo-Ocampo S. A Patient with Bone Fragility, Multiple Fractures, Osteosarcoma, and the Variant c.143A>G in the IFITM5 Gene: A Case Report. Orthop Res Rev 2022; 14:453-458. [PMID: 36467431 PMCID: PMC9717602 DOI: 10.2147/orr.s385146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/18/2022] [Indexed: 09/10/2024] Open
Abstract
Osteogenesis imperfecta (OI) is a group of genetic skeletal disorders, with a prevalence of 1 in 15,000-20,000 births. OI type V has been described in approximately 150 cases and all patients carry the variant (c.-14C> T) in the IFITM5 gene. However, two other variants, p.S40L and p.N48S have been reported in this gene, leading to clinical phenotypes different from OI type V. Here we described a patient with multiple bone fractures, scoliosis, skull alteration (plagiocephaly), bone deformation, bone rickets, and intramedullary epithelioid osteosarcoma that bears the recently reported heterozygous variant c.143A>G (p.N48S) in the IFITM5 gene. This case supports the pathogenicity of this new variant in the IFITM5 gene and adds information regarding its clinical phenotype.
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Affiliation(s)
- Harry Pachajoa
- Genetics Division, Fundación Valle del Lili, Cali, Colombia
- Centro de Investigaciones en Anomalías Congénitas y Enfermedades Raras (CIACER), Universidad Icesi, Cali, Colombia
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23
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Friedlová N, Zavadil Kokáš F, Hupp TR, Vojtěšek B, Nekulová M. IFITM protein regulation and functions: Far beyond the fight against viruses. Front Immunol 2022; 13:1042368. [PMID: 36466909 PMCID: PMC9716219 DOI: 10.3389/fimmu.2022.1042368] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 10/27/2022] [Indexed: 07/30/2023] Open
Abstract
Interferons (IFNs) are important cytokines that regulate immune responses through the activation of hundreds of genes, including interferon-induced transmembrane proteins (IFITMs). This evolutionarily conserved protein family includes five functionally active homologs in humans. Despite the high sequence homology, IFITMs vary in expression, subcellular localization and function. The initially described adhesive and antiproliferative or pro-oncogenic functions of IFITM proteins were diluted by the discovery of their antiviral properties. The large set of viruses that is inhibited by these proteins is constantly expanding, as are the possible mechanisms of action. In addition to their beneficial antiviral effects, IFITM proteins are often upregulated in a broad spectrum of cancers. IFITM proteins have been linked to most hallmarks of cancer, including tumor cell proliferation, therapeutic resistance, angiogenesis, invasion, and metastasis. Recent studies have described the involvement of IFITM proteins in antitumor immunity. This review summarizes various levels of IFITM protein regulation and the physiological and pathological functions of these proteins, with an emphasis on tumorigenesis and antitumor immunity.
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Affiliation(s)
- Nela Friedlová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
| | - Filip Zavadil Kokáš
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
| | - Ted R. Hupp
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
- Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Bořivoj Vojtěšek
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
| | - Marta Nekulová
- Research Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czechia
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24
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Does the c.-14C>T Mutation in the IFITM5 Gene Provide Identical Phenotypes for Osteogenesis Imperfecta Type V? Data from Russia and a Literature Review. Biomedicines 2022; 10:biomedicines10102363. [PMID: 36289625 PMCID: PMC9598403 DOI: 10.3390/biomedicines10102363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/09/2022] [Accepted: 09/19/2022] [Indexed: 11/18/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a large group of genetically heterogeneous diseases resulting from decreased bone density and an abnormal microarchitecture, which are clinically manifested by abnormal bone fractures. A distinctive clinical feature of this group of diseases is the presence of spontaneous fractures and skeletal deformities. However, the clinical manifestations of different types of OI are characterized by marked polymorphism with variable severity of skeletal and extra-skeletal features. Previous studies have shown that a mutation (c.-14C>T) in the IFITM5 gene is responsible for autosomal dominant OI type V. However, the mutation has a variable expression pattern and marked clinical heterogeneity. In this study, a clinical and genetic analysis of 12 cases with molecularly confirmed OI type V from 12 unrelated families was performed. Significant clinical heterogeneity of the disease with the same molecular defect was detected. In six subjects (50%), there were no classic signs of OI type V (formation of a hyperplastic bone callus, calcification of the interosseous membrane and dislocation of the radial head). In all cases, the mutation occurred de novo.
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25
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Hedjazi G, Guterman-Ram G, Blouin S, Schemenz V, Wagermaier W, Fratzl P, Hartmann MA, Zwerina J, Fratzl-Zelman N, Marini JC. Alterations of bone material properties in growing Ifitm5/BRIL p.S42 knock-in mice, a new model for atypical type VI osteogenesis imperfecta. Bone 2022; 162:116451. [PMID: 35654352 PMCID: PMC11162744 DOI: 10.1016/j.bone.2022.116451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 05/17/2022] [Accepted: 05/25/2022] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Osteogenesis imperfecta (OI) is a heterogenous group of heritable connective tissue disorders characterized by high bone fragility due to low bone mass and impaired bone material properties. Atypical type VI OI is an extremely rare and severe form of bone dysplasia resulting from a loss-of-function mutation (p.S40L) in IFITM5/BRIL,the causative gene of OI type V and decreased osteoblast secretion of pigment epithelium-derived factor (PEDF), as in OI type VI. It is not yet known which alterations at the material level might lead to such a severe phenotype. We therefore characterized bone tissue at the micrometer level in a novel heterozygous Ifitm5/BRIL p.S42L knock-in murine model at 4 and 8 weeks of age. METHODS We evaluated in female mice, total body size, femoral and lumbar bone mineral density (BMD) by dual-energy X-ray absorptiometry. In the femoral bone we examined osteoid deposition by light microscopy, assessed bone histomorphometry and mineralization density distribution by quantitative backscattered electron imaging (qBEI). Osteocyte lacunae were examined by qBEI and the osteocyte lacuno-canalicular network by confocal laser scanning microscopy. Vasculature was examined indirectly by qBEI as 2D porosity in cortex, and as 3D porosity by micro-CT in third trochanter. Collagen orientation was examined by second harmonic generation microscopy. Two-way ANOVA was used to discriminate the effect of age and genotype. RESULTS Ifitm5/BRIL p.S42L female mice are viable, do not differ in body size, fat and lean mass from wild type (WT) littermates but have lower whole-body, lumbar and femoral BMD and multiple fractures. The average and most frequent calcium concentration, CaMean and CaPeak, increased with age in metaphyseal and cortical bone in both genotypes and were always higher in Ifitm5/BRIL p.S42L than in WT, except CaMean in metaphysis at 4 weeks of age. The fraction of highly mineralized bone area, CaHigh, was also increased in Ifitm5/BRIL p.S42L metaphyseal bone at 8 weeks of age and at both ages in cortical bone. The fraction of lowly mineralized bone area, CaLow, decreased with age and was not higher in Ifitm5/BRIL p.S42L, consistent with lack of hyperosteoidosis on histological sections by visual exam. Osteocyte lacunae density was higher in Ifitm5/BRIL p.S42L than WT, whereas canalicular density was decreased. Indirect measurements of vascularity revealed a higher pore density at 4 weeks in cortical bone of Ifitm5/BRIL p.S42L than in WT and at both ages in the third trochanter. Importantly, the proportion of bone area with disordered collagen fibrils was highly increased in Ifitm5/BRIL p.S42L at both ages. CONCLUSIONS Despite normal skeletal growth and the lack of a collagen gene mutation, the Ifitm5/BRIL p.S42L mouse shows major OI-related bone tissue alterations such as hypermineralization of the matrix and elevated osteocyte porosity. Together with the disordered lacuno-canalicular network and the disordered collagen fibril orientation, these abnormalities likely contribute to overall bone fragility.
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Affiliation(s)
- Ghazal Hedjazi
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria
| | - Gali Guterman-Ram
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, USA
| | - Stéphane Blouin
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria
| | - Victoria Schemenz
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Am Mühlenberg 1, 14476 Potsdam, Germany
| | - Wolfgang Wagermaier
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Am Mühlenberg 1, 14476 Potsdam, Germany
| | - Peter Fratzl
- Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Am Mühlenberg 1, 14476 Potsdam, Germany
| | - Markus A Hartmann
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria; Vienna Bone and Growth Center, 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, Heinrich Collin Strasse 30, 1140 Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Heinrich Collin Strasse 30, 1140 Vienna, Austria; Vienna Bone and Growth Center, Vienna, Austria
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, USA.
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Thornley P, Bishop N, Baker D, Brock J, Arundel P, Burren C, Smithson S, DeVile C, Crowe B, Allgrove J, Saraff V, Shaw N, Balasubramanian M. Non-collagen pathogenic variants resulting in the osteogenesis imperfecta phenotype in children: a single-country observational cohort study. Arch Dis Child 2022; 107:486-490. [PMID: 34750202 DOI: 10.1136/archdischild-2021-322911] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 10/21/2021] [Indexed: 11/03/2022]
Abstract
BACKGROUND/OBJECTIVES In England, children (0-18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a 'Highly Specialised Service' (HSS OI); affected children with a genetic origin for their disease that is not in COL1A1 or COL1A2 form the majority of the 'atypical' group, which has set criteria for entry into the service. We have used the data from the service to assess the range and frequency of non-collagen pathogenic variants resulting in OI in a single country. METHODS Children with atypical OI were identified through the HSS OI service database. All genetic testing for children with OI in the service were undertaken at the Sheffield Diagnostic Genetics Service. Variant data were extracted and matched to individual patients. This study was done as part of a service evaluation project registered with the Sheffield Children's Hospital Clinical Governance Department. RESULTS One hundred of 337 children in the HSS met the 'atypical' criteria. Eighty have had genetic testing undertaken; 72 had genetic changes detected, 67 in 13 genes known to be causative for OI. The most frequently affected genes were IFITM5 (22), P3H1 (12), SERPINF1 (8) and BMP1 (6). CONCLUSION Among children with more severe forms of OI (approximately one-third of all children with OI), around 20% have pathogenic variants in non-collagen genes. IFITM5 was the most commonly affected gene, followed by genes within the P3H1 complex. These data provide additional information regarding the likelihood of different genetic origins of the disease in children with OI, which may influence clinical care.
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Affiliation(s)
- Patrick Thornley
- The University of Sheffield Faculty of Medicine Dentistry and Health, Sheffield, UK
| | - Nicholas Bishop
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK.,Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
| | - Duncan Baker
- Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Joanna Brock
- Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Paul Arundel
- Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK
| | - Christine Burren
- Department of Paediatric Endocrinology and Diabetes, Bristol Royal Hospital for Children, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Sarah Smithson
- Department of Clinical Genetics, St Michaels Hospital, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Catherine DeVile
- Department of Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Belinda Crowe
- Department of Neurosciences, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Jeremy Allgrove
- Department of Endocrinology, Great Ormond Street Hospital For Children NHS Foundation Trust, London, UK
| | - Vrinda Saraff
- Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Nick Shaw
- Department of Endocrinology and Diabetes, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.,Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Meena Balasubramanian
- Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK .,Highly Specialised Osteogenesis Imperfecta Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.,Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
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Kang H, Aryal AC S, Barnes AM, Martin A, David V, Crawford SE, Marini JC. Antagonism Between PEDF and TGF-β Contributes to Type VI Osteogenesis Imperfecta Bone and Vascular Pathogenesis. J Bone Miner Res 2022; 37:925-937. [PMID: 35258129 PMCID: PMC11152058 DOI: 10.1002/jbmr.4540] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 02/18/2022] [Accepted: 03/04/2022] [Indexed: 11/08/2022]
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder of bone and connective tissue, also known as brittle bone disease. Null mutations in SERPINF1, which encodes pigment epithelium-derived factor (PEDF), cause severe type VI OI, characterized by accumulation of unmineralized osteoid and a fish-scale pattern of bone lamellae. Although the potent anti-angiogenic activity of PEDF has been extensively studied, the disease mechanism of type VI OI is not well understood. Using Serpinf1(-/-) mice and primary osteoblasts, we demonstrate that loss of PEDF delays osteoblast maturation as well as extracellular matrix (ECM) mineralization. Barium sulfate perfusion reveals significantly increased vessel density in the tibial periosteum of Serpinf1(-/-) mouse compared with wild-type littermates. The increased bone vascularization in Serpinf1(-/-) mice correlated with increased number of CD31(+)/Endomucin(+) endothelial cells, which are involved in the coupling angiogenesis and osteogenesis. Global transcriptome analysis by RNA-Seq of Serpinf1(-/-) mouse osteoblasts reveals osteogenesis and angiogenesis as the biological processes most impacted by loss of PEDF. Intriguingly, TGF-β signaling is activated in type VI OI cells, and Serpinf1(-/-) osteoblasts are more sensitive to TGF-β stimulation than wild-type osteoblasts. TGF-β stimulation and PEDF deficiency showed additive effects on transcription suppression of osteogenic markers and stimulation of pro-angiogenic factors. Furthermore, PEDF attenuated TGF-β-induced expression of pro-angiogenic factors. These data suggest that functional antagonism between PEDF and TGF-β pathways controls osteogenesis and bone vascularization and is implicated in type VI OI pathogenesis. This antagonism may be exploited in developing therapeutics for type VI OI utilizing PEDF and TGF-β antibody. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
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Affiliation(s)
- Heeseog Kang
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, MD, USA
| | - Smriti Aryal AC
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, MD, USA
| | - Aileen M Barnes
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, MD, USA
| | - Aline Martin
- Division of Nephrology and Hypertension, Department of Medicine, and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Valentin David
- Division of Nephrology and Hypertension, Department of Medicine, and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Susan E Crawford
- Department of Surgery, NorthShore University HealthSystem Research Institute, Affiliate of University of Chicago Pritzker School of Medicine, Evanston, IL, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, NICHD, NIH, Bethesda, MD, USA
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Schindeler A, Lee LR, O'Donohue AK, Ginn SL, Munns CF. Curative Cell and Gene Therapy for Osteogenesis Imperfecta. J Bone Miner Res 2022; 37:826-836. [PMID: 35306687 PMCID: PMC9324990 DOI: 10.1002/jbmr.4549] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/03/2022] [Accepted: 02/27/2022] [Indexed: 11/17/2022]
Abstract
Osteogenesis imperfecta (OI) describes a series of genetic bone fragility disorders that can have a substantive impact on patient quality of life. The multidisciplinary approach to management of children and adults with OI primarily involves the administration of antiresorptive medication, allied health (physiotherapy and occupational therapy), and orthopedic surgery. However, advances in gene editing technology and gene therapy vectors bring with them the promise of gene-targeted interventions to provide an enduring or perhaps permanent cure for OI. This review describes emergent technologies for cell- and gene-targeted therapies, major hurdles to their implementation, and the prospects of their future success with a focus on bone disorders. © 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)
- Aaron Schindeler
- Bioengineering and Molecular Medicine Laboratorythe Children's Hospital at Westmead and the Westmead Institute for Medical ResearchWestmeadAustralia
- Children's Hospital Westmead Clinical SchoolUniversity of SydneyCamperdownAustralia
| | - Lucinda R Lee
- Bioengineering and Molecular Medicine Laboratorythe Children's Hospital at Westmead and the Westmead Institute for Medical ResearchWestmeadAustralia
- Children's Hospital Westmead Clinical SchoolUniversity of SydneyCamperdownAustralia
| | - Alexandra K O'Donohue
- Bioengineering and Molecular Medicine Laboratorythe Children's Hospital at Westmead and the Westmead Institute for Medical ResearchWestmeadAustralia
- Children's Hospital Westmead Clinical SchoolUniversity of SydneyCamperdownAustralia
| | - Samantha L Ginn
- Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and HealthThe University of Sydney and Sydney Children's Hospitals NetworkWestmeadAustralia
| | - Craig F Munns
- Faculty of MedicineThe University of QueenslandBrisbaneQLDAustralia
- Department of Endocrinology and DiabetesQueensland Children's HospitalBrisbaneQLDAustralia
- Child Health Research Centre and Faculty of MedicineThe University of QueenslandBrisbaneQueenslandAustralia
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Garg B, Tomar N, Biswas A, Mehta N, Malhotra R. Understanding Musculoskeletal Disorders Through Next-Generation Sequencing. JBJS Rev 2022; 10:01874474-202204000-00001. [PMID: 35383688 DOI: 10.2106/jbjs.rvw.21.00165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
» An insight into musculoskeletal disorders through advancements in next-generation sequencing (NGS) promises to maximize benefits and improve outcomes through improved genetic diagnosis. » The primary use of whole exome sequencing (WES) for musculoskeletal disorders is to identify functionally relevant variants. » The current evidence has shown the superiority of NGS over conventional genotyping for identifying novel and rare genetic variants in patients with musculoskeletal disorders, due to its high throughput and low cost. » Genes identified in patients with scoliosis, osteoporosis, osteoarthritis, and osteogenesis imperfecta using NGS technologies are listed for further reference.
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Affiliation(s)
- Bhavuk Garg
- Department of Orthopaedics, All India Institute of Medical Sciences, New Delhi, India
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Ahmad N, Aleysae NA, Sobaihi M, Naitah N, Rasol MA, Al-Kouatli AA, Almaghamsi TM, Heaphy ELG, Attiyah MH, Hrays M, Alghamdi B, Alzahrani AS. A single-centre study of genetic mutations, audiology, echocardiogram and pulmonary function in Saudi children with osteogenesis imperfecta. J Pediatr Endocrinol Metab 2022; 35:355-362. [PMID: 34954934 DOI: 10.1515/jpem-2021-0587] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 11/25/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Osteogenesis imperfecta (OI) is a heterogeneous group of inherited connective tissue disorders, characterised by skeletal fragility. Patients with OI may also exhibit extra-skeletal features like blue or grey scleral colour, fragile skin, easy bruising, joint laxity, short stature, deafness, cardiac valve abnormalities and abnormal pulmonary function. The objective of this study is to describe genetic mutations, prevalence of hearing issues, cardiac complications and impaired pulmonary function in children with OI. METHODS This is a cross-sectional study of 23 Saudi children aged 6 months to 18 years who were diagnosed with OI. The revised Sillence classification (2,105) was used to classify the OI type. Whole exome sequencing was performed for genetic mutations. The hearing was assessed by either pure-tone audiometry and/or otoacoustic emission testing. Cardiac defects were screened by echocardiograms. Spirometry was performed to assess pulmonary function. Data were analysed with descriptive statistics. RESULTS Based on the Sillence classification, 16 patients had OI type III, 6 had type IV and 1 had type I. Of the18 patients who had genetic sequencing, 66.6% had autosomal dominant and 33.3% had autosomal recessive mutations. Among children who had screening, hearing loss was diagnosed in 53% (9/17), congenital cardiac malformations in 26% (5/19) and restrictive lung disease in 70% (7/10). CONCLUSIONS We found significant extra-skeletal features and a high yield of genetic mutations associated with OI. We suggest further studies to develop a screening protocol for extra-skeletal features in children with OI.
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Affiliation(s)
- Noman Ahmad
- King Faisal Specialist Hospital & Research Centre (Gen. Org.), Jeddah, Saudi Arabia
| | | | | | | | - Mohammed Amin Rasol
- King Faisal Specialist Hospital & Research Centre (Gen. Org.), Jeddah, Saudi Arabia
| | | | | | | | | | | | - Balgees Alghamdi
- Molecular Oncology Department, King Faisal Specialist Hospital & Research Centre (Gen. Org.), Riyadh, Saudi Arabia
| | - Ali Saeed Alzahrani
- Research Centre, King Faisal Specialist Hospital & Research Centre (Gen. Org.), Jeddah, Saudi Arabia
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The Osteogenesis Imperfecta Type V Mutant BRIL/IFITM5 Promotes Transcriptional Activation of MEF2, NFATc, and NR4A in Osteoblasts. Int J Mol Sci 2022; 23:ijms23042148. [PMID: 35216266 PMCID: PMC8875491 DOI: 10.3390/ijms23042148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 11/18/2022] Open
Abstract
BRIL (bone restricted ifitm-like; also known as IFITM5) is a transmembrane protein expressed in osteoblasts. Although its role in skeletal development and homeostasis is unknown, mutations in BRIL result in rare dominant forms of osteogenesis imperfecta. The pathogenic mechanism has been proposed to be a gain-of or neomorphic function. To understand the function of BRIL and its OI type V mutant (MALEP BRIL) and whether they could activate signaling pathways in osteoblasts, we performed a luciferase reporter assay screen based on the activity of 26 transcription factors. When overexpressed in MC3T3-E1 and MLO-A5 cells, the MALEP BRIL activated the reporters dependent on MEF2, NFATc, and NR4A significantly more. Additional co-transfection experiments with MEF2C and NFATc1 and a number of their modulators (HDAC4, calcineurin, RCAN, FK506) confirmed the additive or synergistic activation of the pathways by MALEP, and suggested a coordinated regulation involving calcineurin. Endogenous levels of Nr4a members, as well as Ptgs2, were upregulated by MALEP BRIL. Y2H and co-immunoprecipitation indicated that BRIL interacted with CAML, but its contribution as the most upstream stimulator of the Ca2+-calcineurin-MEF2/NFATc cascade was not confirmed convincingly. Altogether the data presented provide the first ever readout to monitor for BRIL activity and suggest a potential gain-of-function causative effect for MALEP BRIL in OI type V, leading to perturbed signaling events and gene expression.
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Jovanovic M, Guterman-Ram G, Marini JC. Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types. Endocr Rev 2022; 43:61-90. [PMID: 34007986 PMCID: PMC8755987 DOI: 10.1210/endrev/bnab017] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous skeletal dysplasia characterized by bone fragility, growth deficiency, and skeletal deformity. Previously known to be caused by defects in type I collagen, the major protein of extracellular matrix, it is now also understood to be a collagen-related disorder caused by defects in collagen folding, posttranslational modification and processing, bone mineralization, and osteoblast differentiation, with inheritance of OI types spanning autosomal dominant and recessive as well as X-linked recessive. This review provides the latest updates on OI, encompassing both classical OI and rare forms, their mechanism, and the signaling pathways involved in their pathophysiology. There is a special emphasis on mutations in type I procollagen C-propeptide structure and processing, the later causing OI with strikingly high bone mass. Types V and VI OI, while notably different, are shown to be interrelated by the interferon-induced transmembrane protein 5 p.S40L mutation that reveals the connection between the bone-restricted interferon-induced transmembrane protein-like protein and pigment epithelium-derived factor pathways. The function of regulated intramembrane proteolysis has been extended beyond cholesterol metabolism to bone formation by defects in regulated membrane proteolysis components site-2 protease and old astrocyte specifically induced-substance. Several recently proposed candidate genes for new types of OI are also presented. Discoveries of new OI genes add complexity to already-challenging OI management; current and potential approaches are summarized.
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Affiliation(s)
- Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Gali Guterman-Ram
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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Nadyrshina D, Zaripova A, Tyurin A, Minniakhmetov I, Zakharova E, Khusainova R. Osteogenesis Imperfecta: Search for Mutations in Patients from the Republic of Bashkortostan (Russia). Genes (Basel) 2022; 13:genes13010124. [PMID: 35052464 PMCID: PMC8774438 DOI: 10.3390/genes13010124] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/30/2021] [Accepted: 01/01/2022] [Indexed: 02/04/2023] Open
Abstract
Osteogenesis imperfecta (OI) is an inherited disease of bone characterized by increased bone fragility. Here, we report the results of the molecular architecture of osteogenesis imperfecta research in patients from Bashkortostan Republic, Russia. In total, 16 mutations in COL1A1, 11 mutations in COL1A2, and 1 mutation in P3H1 and IFIMT5 genes were found in isolated states; 11 of them were not previously reported in literature. We found mutations in CLCN7, ALOX12B, PLEKHM1, ERCC4, ARSB, PTH1R, and TGFB1 that were not associated with OI pathogenesis in patients with increased bone fragility. Additionally, we found combined mutations (c.2869C>T, p. Gln957* in COL1A1 and c.1197+5G>A in COL1A2; c.579delT, p. Gly194fs in COL1A1 and c.1197+5G>A in COL1A2; c.2971G>C, p. Gly991Arg in COL1A2 and c.212G>C, p.Ser71Thr in FGF23; c.-14C>T in IFITM5 and c.1903C>T, p. Arg635* in LAMB3) in 4 patients with typical OI clinic phenotypes.
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Affiliation(s)
- Dina Nadyrshina
- Institute of Biochemistry and Genetics—Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, 450054 Ufa, Russia; (A.Z.); (I.M.); (R.K.)
- Departament of Genetics and Fundamental Medicine, Bashkir State University, 450076 Ufa, Russia
- Correspondence: ; Tel.:+7-9033559907
| | - Aliya Zaripova
- Institute of Biochemistry and Genetics—Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, 450054 Ufa, Russia; (A.Z.); (I.M.); (R.K.)
- Republican Medical Genetics Centre, 450076 Ufa, Russia
| | - Anton Tyurin
- Internal Medicine Department, Bashkir State Medical University, 450008 Ufa, Russia;
| | - Ildar Minniakhmetov
- Institute of Biochemistry and Genetics—Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, 450054 Ufa, Russia; (A.Z.); (I.M.); (R.K.)
- Republican Medical Genetics Centre, 450076 Ufa, Russia
- Internal Medicine Department, Bashkir State Medical University, 450008 Ufa, Russia;
| | | | - Rita Khusainova
- Institute of Biochemistry and Genetics—Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences, 450054 Ufa, Russia; (A.Z.); (I.M.); (R.K.)
- Republican Medical Genetics Centre, 450076 Ufa, Russia
- Internal Medicine Department, Bashkir State Medical University, 450008 Ufa, Russia;
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Ludwig K, Seiltgens C, Ibba A, Saran N, Ouellet JA, Glorieux F, Rauch F. Craniocervical abnormalities in osteogenesis imperfecta type V. Osteoporos Int 2022; 33:177-183. [PMID: 34350492 DOI: 10.1007/s00198-021-06088-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: 04/23/2021] [Accepted: 07/30/2021] [Indexed: 11/28/2022]
Abstract
UNLABELLED Craniocervical abnormalities in osteogenesis imperfecta (OI) such as basilar invagination or cervical kyphosis can cause severe neurological morbidity. These abnormalities may be more frequent in OI type V compared with other OI subtypes of similar disease severity, underlining the importance of screening in this group. INTRODUCTION Craniocervical abnormalities in osteogenesis imperfecta (OI) can cause severe neurological morbidity. Although radiological cranial base abnormalities in OI have been well described in the literature, there are limited data on these abnormalities in OI type V and their association with clinical sequelae. METHODS A retrospective case series on patients with craniocervical abnormalities in OI type V at our institution. RESULTS Craniocervical abnormalities were present in 7 of 37 patients with OI type V (19%). For 5 patients (age at last follow-up: 5 to 26 years; 2 females), sufficient information was available for inclusion in the case series. All had genetically confirmed OI type V. Age range at diagnosis of the craniocervical abnormality was 1 day to 18 years. Basilar invagination was present in 3 patients; 2 had cervical kyphosis. Dysplasia of upper cervical vertebrae or base of skull was seen in 3 patients. The severity of the craniocervical abnormality did not clearly correlate with the severity of the OI phenotype. Three patients required surgical intervention (ages 7, 11, and 26 years) due to compression of the spinal cord or brainstem. Craniocervical abnormalities were detected incidentally or on screening in 3 patients, and only 2 had significant positive findings on neurological examination. CONCLUSION A variety of craniocervical abnormalities are seen in OI type V including dysplasia of the cervical vertebrae. These cases highlight the importance of screening patients with OI type V with lateral skull and cervical spine x-rays throughout childhood and after skeletal maturity.
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Affiliation(s)
- K Ludwig
- Shriners Hospitals for Children, 1003 Boulevard Decarie, Montreal, QC, H4A 0A9, Canada
- Department of Pediatrics, McGill University, Montreal, QC, Canada
| | - C Seiltgens
- Shriners Hospitals for Children, 1003 Boulevard Decarie, Montreal, QC, H4A 0A9, Canada
- Department of Pediatrics, McGill University, Montreal, QC, Canada
| | - A Ibba
- Shriners Hospitals for Children, 1003 Boulevard Decarie, Montreal, QC, H4A 0A9, Canada
- Department of Pediatrics, McGill University, Montreal, QC, Canada
| | - N Saran
- Shriners Hospitals for Children, 1003 Boulevard Decarie, Montreal, QC, H4A 0A9, Canada
- Department of Pediatric Surgery, McGill University, Montreal, QC, Canada
- Department of Surgery, Division of Orthopaedic Surgery, McGill University, Montreal, QC, Canada
| | - J A Ouellet
- Shriners Hospitals for Children, 1003 Boulevard Decarie, Montreal, QC, H4A 0A9, Canada
- Department of Pediatric Surgery, McGill University, Montreal, QC, Canada
- Department of Surgery, Division of Orthopaedic Surgery, McGill University, Montreal, QC, Canada
| | - F Glorieux
- Shriners Hospitals for Children, 1003 Boulevard Decarie, Montreal, QC, H4A 0A9, Canada
- Department of Pediatrics, McGill University, Montreal, QC, Canada
- Department of Surgery, Division of Orthopaedic Surgery, McGill University, Montreal, QC, Canada
| | - F Rauch
- Shriners Hospitals for Children, 1003 Boulevard Decarie, Montreal, QC, H4A 0A9, Canada.
- Department of Pediatrics, McGill University, Montreal, QC, Canada.
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Mäkitie RE, Pekkinen M, Morisada N, Kobayashi D, Yonezawa Y, Nishimura G, Ikegawa S, Mäkitie O. A Novel IFITM5 Variant Associated with Phenotype of Osteoporosis with Calvarial Doughnut Lesions: A Case Report. Calcif Tissue Int 2021; 109:626-632. [PMID: 34156493 PMCID: PMC8531111 DOI: 10.1007/s00223-021-00878-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 06/10/2021] [Indexed: 11/29/2022]
Abstract
Osteogenesis imperfecta (OI) and other decreased bone density disorders comprise a heterogeneous group of heritable diseases with skeletal fragility. Recently, it was discovered that mutations in SGMS2, encoding sphingomyelin synthetase 2, result in aberrant sphingomyelin metabolism and lead to a novel form of OI termed osteoporosis with calvarial doughnut lesions (OP-CDL) with moderate to severe skeletal fragility and variable cranial hyperostotic lesions. This study describes a Japanese family with the skeletal phenotype of OP-CDL. The affected individuals have moderately severe, childhood-onset skeletal fragility with multiple long-bone fractures, scoliosis and bone deformities. In addition, they exhibit multiple CDLs or calvarial bumps with central radiolucency and peripheral radiopacity. However, SGMS2 sequencing was normal. Instead, whole-exome sequencing identified a novel IFITM5 missense mutation c.143A>G (p.N48S) (classified as a VUS by ACMG). IFITM5 encodes an osteoblast-restricted protein BRIL and a recurrent c.-14C>T mutation in its 5' UTR region results in OI type V, a distinctive subtype of OI associated with hyperplastic callus formation and ossification of the interosseous membranes. The patients described here have a phenotype clearly different from OI type V and with hyperostotic cranial lesions, feature previously unreported in association with IFITM5. Our findings expand the genetic spectrum of OP-CDL, indicate diverse phenotypic consequences of pathogenic IFITM5 variants, and imply an important role for BRIL in cranial skeletogenesis.
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Affiliation(s)
- R E Mäkitie
- Folkhälsan Institute of Genetics, University of Helsinki, P.O. Box 63, FIN-00014, 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.
| | - M Pekkinen
- Folkhälsan Institute of Genetics, University of Helsinki, P.O. Box 63, FIN-00014, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - N Morisada
- Department of Clinical Genetics, Hyogo Prefectural Kobe Children's Hospital, Kobe, Hyogo, Japan
| | - D Kobayashi
- Department of Orthopaedic Surgery, Hyogo Prefectural Kobe Children's Hospital, Kobe, Hyogo, Japan
| | - Y Yonezawa
- Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences,, Yokohama, Japan
| | - G Nishimura
- Center for Intractable Disease, Saitama Medical University Hospital, Saitama, Japan
| | - S Ikegawa
- Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences,, Yokohama, Japan
| | - O Mäkitie
- Folkhälsan Institute of Genetics, University of Helsinki, P.O. Box 63, FIN-00014, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Children's Hospital, University and Helsinki University Hospital, Helsinki, Finland
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Carroll RS, Donenfeld P, McGreal C, Franzone JM, Kruse RW, Preedy C, Costa J, Dirnberger DR, Bober MB. Comprehensive pain management strategy for infants with moderate to severe osteogenesis imperfecta in the perinatal period. PAEDIATRIC AND NEONATAL PAIN 2021; 3:156-162. [PMID: 35548555 PMCID: PMC8975205 DOI: 10.1002/pne2.12066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 11/15/2022]
Abstract
Osteogenesis imperfecta (OI) is a rare genetic heterogeneous disorder that causes increased bone fragility and recurrent fractures. For infants with OI and diffuse fractures, pain management, which is nuanced and specific for this population, is of the utmost importance to their neonatal care. Through experience at our center, we have developed a standard approach that has been successful in optimizing survival for these infants during this tenuous period. In this paper, we outline our multidisciplinary approach to pain management for infants with moderate to severe OI during the neonatal period, with emphasis on promotion of fracture healing and adequate pain control.
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Affiliation(s)
- Ricki S. Carroll
- Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia Pennsylvania USA
- Division of Palliative Medicine Department of Pediatrics Nemours Children’s Hospital Delaware Wilmington Delaware USA
- Division of Orthogenetics Department of Pediatrics Nemours Children’s Hospital Delaware Wilmington Delaware USA
| | - Perri Donenfeld
- Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia Pennsylvania USA
- Division of Palliative Medicine Department of Pediatrics Nemours Children’s Hospital Delaware Wilmington Delaware USA
| | - Cristina McGreal
- Division of Orthogenetics Department of Pediatrics Nemours Children’s Hospital Delaware Wilmington Delaware USA
| | - Jeanne M. Franzone
- Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia Pennsylvania USA
- Neonatal‐Perinatal Medicine Department of Pediatrics Nemours Children’s Hospital Delaware Wilmington Delaware USA
| | - Richard W. Kruse
- Neonatal‐Perinatal Medicine Department of Pediatrics Nemours Children’s Hospital Delaware Wilmington Delaware USA
| | - Catherine Preedy
- Department of Orthopaedic Surgery Nemours Children’s Hospital Delaware Wilmington Delaware USA
| | - Joanna Costa
- Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia Pennsylvania USA
- Department of Orthopaedic Surgery Nemours Children’s Hospital Delaware Wilmington Delaware USA
| | - Daniel R. Dirnberger
- Department of Orthopaedic Surgery Nemours Children’s Hospital Delaware Wilmington Delaware USA
| | - Michael B. Bober
- Sidney Kimmel Medical College at Thomas Jefferson University Philadelphia Pennsylvania USA
- Division of Orthogenetics Department of Pediatrics Nemours Children’s Hospital Delaware Wilmington Delaware USA
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Lindsay SE, Nicol LE, Gamayo AC, Raney EM. An Unusual Presentation of Osteogenesis Imperfecta: A Case Report. JBJS Case Connect 2021; 11:01709767-202112000-00059. [PMID: 34807880 DOI: 10.2106/jbjs.cc.21.00480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
CASE We report an 18-year-old patient with a clinical phenotype consistent with severe osteogenesis imperfecta (OI) with frequent fractures, short stature, shortening and bowing of extremities, and unusual radiographic features of severe fibrous dysplasia, including lytic lesions and a "ground-glass" appearance. Genetic testing for the patient was notable for a c.119C>T (p.Ser40Leu) variant in exon 1 of IFITM5 and a c.676C>A (Pro226Thr) variant in exon 5 of CREB3L1. CONCLUSION This unusual skeletal presentation was in the setting of a rare IFITM5 mutation and represents a unique case of severe OI.
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Affiliation(s)
| | | | | | - Ellen M Raney
- Shriners Hospitals for Children-Portland, Portland, Oregon
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38
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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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Abstract
Osteogenesis imperfecta (OI) is a disease characterised by altered bone tissue material properties together with abnormal micro and macro-architecture and thus bone fragility, increased bone turnover and hyperosteocytosis. Increasingly appreciated are the soft tissue changes, sarcopenia in particular. Approaches to treatment are now multidisciplinary, with bisphosphonates having been the primary pharmacological intervention over the last 20 years. Whilst meta-analyses suggest that anti-fracture efficacy across the life course is equivocal, there is good evidence that for children bisphosphonates reduce fracture risk, increase vertebral size and improve vertebral shape, as well as improving motor function and mobility. The genetics of OI continues to provide insights into the molecular pathogenesis of the disease, although the pathophysiology is less clear. The complexity of the multi-scale interactions of bone tissue with cellular function are gradually being disentangled, but the fundamental question of why increased tissue brittleness should be associated with so many other changes is unclear; ER stress, pro-inflammatory cytokines, accelerated senesence and altered matrix component release might all contribute, but a unifying hypothesis remains elusive. New approaches to therapy are focussed on increasing bone mass, following the paradigm established by the treatment of postmenopausal osteoporosis. For adults, this brings the prospect of restoring previously lost bone - for children, particularly at the severe end of the spectrum, the possibility of further reducing fracture frequency and possibly altering growth and long term function are attractive. The alternatives that might affect tissue brittleness are autophagy enhancement (through the removal of abnormal type I collagen aggregates) and stem cell transplantation - both still at the preclinical stage of assessment. Preclinical assessment is not supportive of targeting inflammatory pathways, although understanding why TGFb signalling is increased, and whether that presents a treatment target in OI, remains to be established.
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Affiliation(s)
- Fawaz Arshad
- Academic Unit of Child Health, Sheffield Children's Hospital, Department of Oncology and Metabolism, University of Sheffield, S10 2TH, UK
| | - Nick Bishop
- Academic Unit of Child Health, Sheffield Children's Hospital, Department of Oncology and Metabolism, University of Sheffield, S10 2TH, UK.
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40
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Moffatt P, Boraschi-Diaz I, Marulanda J, Bardai G, Rauch F. Calvaria Bone Transcriptome in Mouse Models of Osteogenesis Imperfecta. Int J Mol Sci 2021; 22:ijms22105290. [PMID: 34069814 PMCID: PMC8157281 DOI: 10.3390/ijms22105290] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/05/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a bone fragility disorder that is usually caused by mutations affecting collagen type I. We compared the calvaria bone tissue transcriptome of male 10-week-old heterozygous Jrt (Col1a1 mutation) and homozygous oim mice (Col1a2 mutation) to their respective littermate results. We found that Jrt and oim mice shared 185 differentially expressed genes (upregulated: 106 genes; downregulated: 79 genes). A total of seven genes were upregulated by a factor of two or more in both mouse models (Cyp2e1, Slc13a5, Cgref1, Smpd3, Ifitm5, Cthrc1 and Rerg). One gene (Gypa, coding for a blood group antigen) was downregulated by a factor of two or more in both OI mouse models. Overrepresentation analyses revealed that genes involved in ‘ossification’ were significantly overrepresented among upregulated genes in both Jrt and oim mice, whereas hematopoietic genes were downregulated. Several genes involved in Wnt signaling and transforming growth factor beta signaling were upregulated in oim mice, but less so in Jrt mice. Thus, this study identified a set of genes that are dysregulated across various OI mouse models and are likely to play an important role in the pathophysiology of this disorder.
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Affiliation(s)
- Pierre Moffatt
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (P.M.); (I.B.-D.); (J.M.); (G.B.)
- Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada
| | - Iris Boraschi-Diaz
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (P.M.); (I.B.-D.); (J.M.); (G.B.)
- Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
| | - Juliana Marulanda
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (P.M.); (I.B.-D.); (J.M.); (G.B.)
- Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
| | - Ghalib Bardai
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (P.M.); (I.B.-D.); (J.M.); (G.B.)
| | - Frank Rauch
- Shriners Hospital for Children-Canada, Montreal, QC H4A 0A9, Canada; (P.M.); (I.B.-D.); (J.M.); (G.B.)
- Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
- Correspondence: ; Tel.: +1-514-282-7193
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41
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Higuchi Y, Hasegawa K, Futagawa N, Yamashita M, Tanaka H, Tsukahara H. Genetic analysis in Japanese patients with osteogenesis imperfecta: Genotype and phenotype spectra in 96 probands. Mol Genet Genomic Med 2021; 9:e1675. [PMID: 33939306 PMCID: PMC8222851 DOI: 10.1002/mgg3.1675] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 02/14/2021] [Accepted: 03/23/2021] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Osteogenesis imperfecta (OI) is a rare connective-tissue disorder characterized by bone fragility. Approximately 90% of all OI cases are caused by variants in COL1A1 or COL1A2. Additionally, IFITM5 variants are responsible for the unique OI type 5. We previously analyzed COL1A1/2 variants in 22 Japanese families with OI through denaturing high-performance liquid chromatography screening, but our detection rate was low (41%). METHODS To expand the genotype-phenotype correlations, we performed a genetic analysis of COL1A1/2 and IFITM5 in 96 non-consanguineous Japanese OI probands by Sanger sequencing. RESULTS Of these individuals, 54, 41, and 1 had type 1 (mild), type 2-4 (moderate-to-severe), and type 5 phenotypes, respectively. In the mild group, COL1A1 nonsense and splice-site variants were prevalent (n = 30 and 20, respectively), but there were also COL1A1 and COL1A2 triple-helical glycine substitutions (n = 2 and 1, respectively). In the moderate-to-severe group, although COL1A1 and COL1A2 glycine substitutions were common (n = 14 and 18, respectively), other variants were also detected. The single case of type 5 had the characteristic c.-14C>T variant in IFITM5. CONCLUSION These results increase our previous detection rate for COL1A1/2 variants to 99% and provide insight into the genotype-phenotype correlations in OI.
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Affiliation(s)
- Yousuke Higuchi
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kosei Hasegawa
- Department of Pediatrics, Okayama University Hospital, Okayama, Japan
| | - Natsuko Futagawa
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Department of Pediatrics, Okayama University Hospital, Okayama, Japan
| | - Miho Yamashita
- Faculty of Human Life Sciences, Notre Dame Seishin University, Okayama, Japan
| | - Hiroyuki Tanaka
- Department of Pediatrics, Okayama Saiseikai General Hospital, Okayama, Japan
| | - Hirokazu Tsukahara
- Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Mähr M, Blouin S, Behanova M, Misof BM, Glorieux FH, Zwerina J, Rauch F, Hartmann MA, Fratzl-Zelman N. Increased Osteocyte Lacunae Density in the Hypermineralized Bone Matrix of Children with Osteogenesis Imperfecta Type I. Int J Mol Sci 2021; 22:ijms22094508. [PMID: 33925942 PMCID: PMC8123504 DOI: 10.3390/ijms22094508] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 12/23/2022] Open
Abstract
Osteocytes are terminally differentiated osteoblasts embedded within the bone matrix and key orchestrators of bone metabolism. However, they are generally not characterized by conventional bone histomorphometry because of their location and the limited resolution of light microscopy. OI is characterized by disturbed bone homeostasis, matrix abnormalities and elevated bone matrix mineralization density. To gain further insights into osteocyte characteristics and bone metabolism in OI, we evaluated 2D osteocyte lacunae sections (OLS) based on quantitative backscattered electron imaging in transiliac bone biopsy samples from children with OI type I (n = 19) and age-matched controls (n = 24). The OLS characteristics were related to previously obtained, re-visited histomorphometric parameters. Moreover, we present pediatric bone mineralization density distribution reference data in OI type I (n = 19) and controls (n = 50) obtained with a field emission scanning electron microscope. Compared to controls, OI has highly increased OLS density in cortical and trabecular bone (+50.66%, +61.73%; both p < 0.001), whereas OLS area is slightly decreased in trabecular bone (−10.28%; p = 0.015). Correlation analyses show a low to moderate, positive association of OLS density with surface-based bone formation parameters and negative association with indices of osteoblast function. In conclusion, hyperosteocytosis of the hypermineralized OI bone matrix associates with abnormal bone cell metabolism and might further impact the mechanical competence of the bone tissue.
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Affiliation(s)
- Matthias Mähr
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Stéphane Blouin
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Martina Behanova
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Barbara M. Misof
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Francis H. Glorieux
- Genetics Unit, Shriners Hospital for Children and McGill University, Montreal, ON H4A 0A9, Canada; (F.H.G.); (F.R.)
| | - Jochen Zwerina
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Frank Rauch
- Genetics Unit, Shriners Hospital for Children and McGill University, Montreal, ON H4A 0A9, Canada; (F.H.G.); (F.R.)
| | - Markus A. Hartmann
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
| | - Nadja Fratzl-Zelman
- 1st Medical Department, Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, Hanusch Hospital, 1140 Vienna, Austria; (M.M.); (S.B.); (M.B.); (B.M.M.); (J.Z.); (M.A.H.)
- Correspondence: ; Tel.: +43-5-9393-55770
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Whyte MP, Aronson J, McAlister WH, Weinstein RS, Wenkert D, Clements KL, Gottesman GS, Madson KL, Stolina M, Bijanki VN, Plotkin H, Huskey M, Duan S, Mumm S. Coalescing expansile skeletal disease: Delineation of an extraordinary osteopathy involving the IFITM5 mutation of osteogenesis imperfecta type V. Bone 2021; 145:115835. [PMID: 33360005 DOI: 10.1016/j.bone.2020.115835] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/08/2020] [Accepted: 12/21/2020] [Indexed: 12/30/2022]
Abstract
In 2003, we briefly reported the remarkable osteopathy of a 12-year-old boy who at age two months began fracturing his limbs with subsequent hyperplastic callus formation and expansion and fusion of appendicular bones. By age ten years he had coalesced his lumbosacral spine, pelvis, femurs, and leg and foot bones as a single structure. Computed tomography of expanded bone revealed a thin cortical shell, diminished irregular trabeculae, and cystic areas. Histopathology featured foci of woven bone, densely packed osteocytes, cartilage, fibrovascular tissue, and massive fat deposition in the marrow space lacking hematogenous precursor cells. Bone turnover markers indicated accelerated remodeling and the few radiographically assessable appendicular bones improved during brief adherence to alendronate therapy. Following puberty, serum multiplex biomarker profiling confirmed accelerated bone turnover. At age 23 years, macrospecimens from leg amputation revealed ossification along capsular tissue together with hyaline cartilage degeneration. Concurrently, the life-long course of this same disorder was delineated in an unrelated woman until her death at age 51 years. Both patients demonstrated the radiographic hallmarks and harbored the heterozygous point mutation (c.-14C>T) in the 5'-UTR of IFITM5 associated with osteogenesis imperfecta type V (OI-V). Herein, we detail the clinical, radiological, histopathological, biochemical, and molecular findings and discuss the etiology and pathogenesis of this extraordinary osteopathy that we call coalescing expansile skeletal disease.
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Affiliation(s)
- Michael P Whyte
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
| | - James Aronson
- Department of Pediatric Orthopaedics, University of Arkansas for Medical Sciences at Arkansas Children's Hospital, Little Rock, AR 72202, USA.
| | - William H McAlister
- Pediatric Radiology Section, Mallinckrodt Institute of Radiology at St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO 63110, USA.
| | - Robert S Weinstein
- Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, Department of Internal Medicine, Little Rock, AR 72201, USA.
| | - Deborah Wenkert
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA.
| | - Karen L Clements
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA.
| | - Gary S Gottesman
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA.
| | - Katherine L Madson
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA
| | - Marina Stolina
- Department of Cardiometabolic Disorders Research, Amgen Inc., Thousand Oaks, CA 91320, USA.
| | - Vinieth N Bijanki
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA.
| | - Horacio Plotkin
- Departments of Pediatrics and Orthopedics, Children's Hospital and University of Nebraska Medical Center, Omaha, NE 68198, USA.
| | - Margaret Huskey
- Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
| | - Shenghui Duan
- Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
| | - Steven Mumm
- Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
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Demir S, Yalçıntepe S, Atlı Eİ, Sanrı A, Yıldırım R, Tütüncüler F, Çelik M, Atlı E, Özemri Sağ Ş, Eker D, Temel Ş, Gürkan H. Targeted High-Throughput Sequencing Analysis Results of Osteogenesis Imperfecta Patients from Different Regions of Turkey. Genet Test Mol Biomarkers 2021; 25:59-67. [PMID: 33470886 DOI: 10.1089/gtmb.2020.0169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective: Osteogenesis imperfecta (OI) includes a group of disorders characterized by susceptibility to bone fractures with different severities. The increasing number of genes that may underlie the disorder, along with the broad phenotypic spectrum that overlaps with other skeletal diseases, provided a compelling case for the use of high-throughput sequencing (HTS) technology as an aid to OI diagnoses. The aim of this analysis was to present the data from our 5-year targeted HTS results, that includes the reporting of 9 novel and 24 known mutations, found in OI patients, from 5 different regions of Turkey. Materials and Methods: We performed a retrospective cross-sectional study, reporting the HTS results of 43 patients (23 female and 20 male; mean age: 9.5 years), directed to our center with a suspicion of OI between February 2015 and May 2020. Genetic analyses were also performed for 24 asymptomatic parents to aid the segregation analyses. We utilized an HTS panel targeting the coding regions of 57 genes associated with a reduction, increase, or abnormal development of bone mineralization. In addition, we sequenced the entire coding region of the IFITM5 gene through HTS. Results: Thirty-nine patients had at least one pathogenic/likely pathogenic variation (90.69%) in the COL1A1 (56.41%), COL1A2 (20.51%), FKBP10 (7.7%), P3H1 (5.13%), IFITM5 (5.13%), CTRAP (2.56%), or TMEM38B (2.56%) genes. Nine of the determined pathogenic/likely pathogenic variations were novel. The recurrent pathogenic mutations were c.1081C>T (p.Arg361Ter) (3/43), c.1405C>T (p.Arg469Ter) (2/43), and c.3749del (p.Gly1250AlafsTer81) in COL1A1 gene, along with c.-14C>T variation in the 5'UTR of the IFITM5 gene (2/43) and the c.890_897dup variation in the FKBP10 gene (2/43). Three out of 43 patients were carrying at least one additional variant of unknown significance, highlighting the importance of a multigene panel approach and segregation analyses. Conclusion: We suggest that a targeted HTS panel is a feasible tool for genetic diagnosis of OI in patients.
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Affiliation(s)
- Selma Demir
- Department of Medical Genetics, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Sinem Yalçıntepe
- Department of Medical Genetics, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Emine İkbal Atlı
- Department of Medical Genetics, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Aslıhan Sanrı
- Department of Pediatrics, Samsun Ondokuz Mayıs Üniversitesi, Samsun, Turkey
| | - Ruken Yıldırım
- Department of Pediatric Endocrinology, Diyarbakır Hospital of Pediatric Diseases, Diyarbakır, Turkey
| | - Filiz Tütüncüler
- Department of Pediatric Endocrinology and Trakya University Faculty of Medicine, Edirne, Turkey
| | - Mehmet Çelik
- Department of Endocrinology, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Engin Atlı
- Department of Medical Genetics, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Şebnem Özemri Sağ
- Department of Medical Genetics, Faculty of Medicine, Uludağ University, Bursa, Turkey
| | - Damla Eker
- Department of Medical Genetics, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Şehime Temel
- Department of Medical Genetics, Faculty of Medicine, Uludağ University, Bursa, Turkey
| | - Hakan Gürkan
- Department of Medical Genetics, Trakya University Faculty of Medicine, Edirne, Turkey
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45
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El-Gazzar A, Högler W. Mechanisms of Bone Fragility: From Osteogenesis Imperfecta to Secondary Osteoporosis. Int J Mol Sci 2021; 22:ijms22020625. [PMID: 33435159 PMCID: PMC7826666 DOI: 10.3390/ijms22020625] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/07/2021] [Accepted: 01/07/2021] [Indexed: 12/13/2022] Open
Abstract
Bone material strength is determined by several factors, such as bone mass, matrix composition, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-ß signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments.
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Affiliation(s)
| | - Wolfgang Högler
- Correspondence: ; Tel.: +43-(0)5-7680-84-22001; Fax: +43-(0)5-7680-84-22004
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46
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Deng Y, Huo Y, Li J. Case Report: Hyperplastic Callus of the Femur Mimicking Osteosarcoma in Osteogenesis Imperfecta Type V. Front Endocrinol (Lausanne) 2021; 12:622674. [PMID: 33935965 PMCID: PMC8082416 DOI: 10.3389/fendo.2021.622674] [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] [Received: 10/30/2020] [Accepted: 01/04/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Osteogenesis imperfecta (OI) type V is a rare form of OI which is often characterized by hyperplastic callus. Misdiagnosis is a possibility due to its rarity and because patients involved are mostly in adolescence, a predisposing age for osteosarcoma. Here, we report this case and aim to improve understanding of patients with OI type V and avoid misdiagnosis. CASE PRESENTATION A male, 14-year-old patient was admitted to Jiangxi Provincial People's Hospital affiliated to Nanchang University in August 2020 due to repeated fractures for more than 11 years and swelling in his right leg for more than 4 years. The patient was diagnosed with OI in 2014 due to repeated fracture and was treated with bisphosphonates. The swelling was accompanied by huge callus formation. Prior to admission to our hospital in 2016 osteosarcoma was suspected by imaging and pathology, and amputation was recommended. OI-V was confirmed after more than four years of follow-up and genetic diagnosis, and the affected limb was preserved. CONCLUSION The history of OI and lack of rapid progression suggested OI-V with a hyperplastic callus. Combined with genetic testing, the diagnosis was OI-V. Although the patient was at a predisposing age for osteosarcoma, diagnosis and treatment should be based on the medical history of the patient, imaging,and genetic testing, and sometimes even time-consuming retrospective observation.
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47
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Cho TJ, Ko JM, Kim H, Shin HI, Yoo WJ, Shin CH. Management of Osteogenesis Imperfecta: A Multidisciplinary Comprehensive Approach. Clin Orthop Surg 2020; 12:417-429. [PMID: 33274017 PMCID: PMC7683189 DOI: 10.4055/cios20060] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 09/28/2020] [Indexed: 12/30/2022] Open
Abstract
Osteogenesis imperfecta (OI) is characterized by recurring fractures and limb and spine deformities. With the advent of medical therapeutics and the discovery of causative genes, as well as the introduction of a newly devised intramedullary rod, the general condition and ambulatory function of patients diagnosed with OI have been improved over the past decades. This review covers recent developments in research and management of OI.
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Affiliation(s)
- Tae-Joon Cho
- Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Min Ko
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyoungmin Kim
- Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyung-Ik Shin
- Department of Rehabilitation Medicine, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Won Joon Yoo
- Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Chang Ho Shin
- Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea
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48
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Effect of immunosuppressants on a mouse model of osteogenesis imperfecta type V harboring a heterozygous Ifitm5 c.-14C > T mutation. Sci Rep 2020; 10:21197. [PMID: 33273604 PMCID: PMC7713238 DOI: 10.1038/s41598-020-78403-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 11/19/2020] [Indexed: 01/08/2023] Open
Abstract
Osteogenesis imperfecta (OI) type V is an autosomal dominant disorder caused by the c.-14C > T mutation in the interferon-induced transmembrane protein 5 gene (IFITM5), however, its onset mechanism remains unclear. In this study, heterozygous c.-14C > T mutant mice were developed to investigate the effect of immunosuppressants (FK506 and rapamycin) on OI type V. Among the mosaic mice generated by Crispr/Cas9-based technology, mice with less than 40% mosaic ratio of c.-14C > T mutation survived, whereas those with more than 48% mosaic ratio exhibited lethal skeletal abnormalities with one exception. All heterozygous mutants obtained by mating mosaic mice with wild-type mice exhibited a perinatal lethal phenotype due to severe skeletal abnormalities. Administration of FK506, a calcineurin inhibitor, in the heterozygous fetuses improved bone mineral content (BMC) of the neonates, although it did not save the neonates from the lethal effects of the mutation, whereas rapamycin, an mTOR inhibitor, reduced BMC, suggesting that mTOR signaling is involved in the bone mineralization of heterozygous mutants. These findings could clarify certain aspects of the onset mechanism of OI type V and enable development of therapeutics for this condition.
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49
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Skarp S, Xia JH, Zhang Q, Löija M, Costantini A, Ruddock LW, Mäkitie O, Wei GH, Männikkö M. Exome Sequencing Reveals a Phenotype Modifying Variant in ZNF528 in Primary Osteoporosis With a COL1A2 Deletion. J Bone Miner Res 2020; 35:2381-2392. [PMID: 32722848 PMCID: PMC7757391 DOI: 10.1002/jbmr.4145] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 06/30/2020] [Accepted: 07/23/2020] [Indexed: 12/12/2022]
Abstract
We studied a family with severe primary osteoporosis carrying a heterozygous p.Arg8Phefs*14 deletion in COL1A2, leading to haploinsufficiency. Three affected individuals carried the mutation and presented nearly identical spinal fractures but lacked other typical features of either osteogenesis imperfecta or Ehlers-Danlos syndrome. Although mutations leading to haploinsufficiency in COL1A2 are rare, mutations in COL1A1 that lead to less protein typically result in a milder phenotype. We hypothesized that other genetic factors may contribute to the severe phenotype in this family. We performed whole-exome sequencing in five family members and identified in all three affected individuals a rare nonsense variant (c.1282C > T/p.Arg428*, rs150257846) in ZNF528. We studied the effect of the variant using qPCR and Western blot and its subcellular localization with immunofluorescence. Our results indicate production of a truncated ZNF528 protein that locates in the cell nucleus as per the wild-type protein. ChIP and RNA sequencing analyses on ZNF528 and ZNF528-c.1282C > T indicated that ZNF528 binding sites are linked to pathways and genes regulating bone morphology. Compared with the wild type, ZNF528-c.1282C > T showed a global shift in genomic binding profile and pathway enrichment, possibly contributing to the pathophysiology of primary osteoporosis. We identified five putative target genes for ZNF528 and showed that the expression of these genes is altered in patient cells. In conclusion, the variant leads to expression of truncated ZNF528 and a global change of its genomic occupancy, which in turn may lead to altered expression of target genes. ZNF528 is a novel candidate gene for bone disorders and may function as a transcriptional regulator in pathways affecting bone morphology and contribute to the phenotype of primary osteoporosis in this family together with the COL1A2 deletion. © 2020 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)
- Sini Skarp
- Infrastructure for Population Studies, Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.,Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.,Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
| | - Ji-Han Xia
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.,Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Qin Zhang
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.,Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Marika Löija
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.,Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
| | - Alice Costantini
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet/Stockholm, Stockholm, Sweden
| | - Lloyd W Ruddock
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
| | - Outi Mäkitie
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet/Stockholm, Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.,Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Folkhälsan Research Center, Genetics Research Program, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Gong-Hong Wei
- Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.,Biocenter Oulu, University of Oulu, Oulu, Finland.,Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Minna Männikkö
- Infrastructure for Population Studies, Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland.,Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
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50
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Pargas C, Franzone JM, Rogers KJ, Artinian F, Santana A, Shah SA, McGreal CM, Kruse RW, Bober MB. Cervical kyphosis: A predominant feature of patients with osteogenesis imperfecta type 5. Bone Rep 2020; 13:100735. [PMID: 33304945 PMCID: PMC7718132 DOI: 10.1016/j.bonr.2020.100735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 11/03/2020] [Accepted: 11/18/2020] [Indexed: 10/26/2022] Open
Abstract
Objectives Osteogenesis imperfecta (OI) is a heterogeneous group of genetic disorders of connective tissue that cause skeletal fragility and extra-skeletal manifestations. Classically, four different types of OI were distinguished. Type 5 OI was added due to its distinct clinical and radiographic features. In 2012, two independent groups identified a recurrent heterozygous c.-14C>T mutation in IFITM5 as the responsible genetic change for this type of OI. To our knowledge, cervical kyphosis has not been identified in the literature as a finding in type 5 OI patients. This is a retrospective review of a cohort of patients with type 5 OI and a description of associated cervical spine deformity. Methods After institutional review board approval, a retrospective review identified 13 patients with type 5 OI. Clinical, radiologic, and genetic data from 2002 to 2020 were reviewed. Results We identified 13 patients with clinical diagnosis of type 5 OI. Twelve had molecular confirmation and the classic IFITM5, c.14C>T gene mutation was identified. The remaining individual did not undergo genetic testing. Dentinogenesis imperfecta was observed in one patient, while blue sclerae or hearing loss were not present. All patients had at least one fracture and four underwent intramedullary rodding. Radiologic features included subphyseal metaphyseal radiodense line in 12/13 patients (92%), interosseous membrane calcification in seven of 13 patients (54%) (more commonly noted in the upper extremities), and hypertrophic callus in six of 13 patients (46%). Thoracolumbar spinal deformities were seen in six of 13 patients (46%) with two of these individuals requiring surgery. Cervical kyphosis was noted in nine of 13 individuals (69%) ranging in age from 3 months to 22 years. Anterior wedging of the cervical vertebral bodies was noted in the absence of any fractures. Six of nine individuals demonstrated listhesis of C2-C3 or C3-C4 segment. Magnetic resonance imaging studies were performed and reviewed in patients with cervical kyphosis and subluxation; three patients showed narrowing of spinal canal without cervical cord compression and one asymptomatic patient showed impingement of the spinal cord. Conclusions Cervical kyphosis appears to be a common feature of type 5 OI. It can be a presenting and apparently life-long association and does not appear to be caused by vertebral body fractures. Evaluation for cervical kyphosis should be performed in patients with a suspected or confirmed diagnosis of type 5 OI. Furthermore, if cervical kyphosis is noted in an individual with OI, type 5 OI should be considered.Level of evidence: IV.
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Affiliation(s)
- Carlos Pargas
- Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Jeanne M Franzone
- Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Kenneth J Rogers
- Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Frank Artinian
- Department of Orthopaedic Surgery, Akron Children's Hospital, Akron, OH, USA
| | - Adolfredo Santana
- Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Suken A Shah
- Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Cristina M McGreal
- Division of Orthogenetics, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Richard W Kruse
- Department of Orthopaedic Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
| | - Michael B Bober
- Division of Orthogenetics, Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA
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