1
|
Saito S, Suzuki S, Izumi K, Kamiyama T, Saito K, Yamamura H, Kokumai T, Furuya A, Taketazu G, Makita Y, Niida Y, Takahashi S. Clinical and Molecular Genetic Analyses of a Girl With Isolated Nephrogenic Diabetes Insipidus due to Contiguous Gene Deletion Involving AVPR2 and L1CAM. Am J Med Genet A 2025; 197:e64024. [PMID: 39992048 DOI: 10.1002/ajmg.a.64024] [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: 06/25/2024] [Revised: 12/29/2024] [Accepted: 01/25/2025] [Indexed: 02/25/2025]
Abstract
Loss-of-function mutations of AVPR2 and L1CAM result in nephrogenic diabetes insipidus (NDI) and L1 syndrome. These diseases are inherited in an X-linked recessive manner. Females with heterozygous variants can be affected owing to skewed X-chromosome inactivation (XCI). A 3-year-old girl with normal development was presented with polydipsia and polyuria, and diagnosed of NDI through an improper response to water restriction and desmopressin administration. A targeted genome capture sequencing for X chromosome confirmed Xq28 microdeletion involving AVPR2 and L1CAM, derived from mother with mosaicism of the deletion. No pathogenic variants were identified in the paternal X allele nor in AQP2, another causative gene of NDI. XCI was exclusively skewed toward the maternal X chromosome in hair, oral mucosa, and blood, while it was random in nails and renal tubular epithelial cells (RTECs). Both AVPR2 and L1CAM mRNA expression in the patient's RTECs were significantly reduced compared to those of controls, with AVPR2 showing a more pronounced decrease. Thus, we demonstrated for the first time that NDI can develop in a female with a AVPR2 deletion despite of random XCI. Moreover, the absence of L1 syndrome in the female patient was caused most probably through organ-dependent skewed XCI in the deletion allele.
Collapse
Affiliation(s)
- Shoma Saito
- Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan
| | - Shigeru Suzuki
- Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan
| | - Kengo Izumi
- Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan
| | - Takumi Kamiyama
- Faculty of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Kosuke Saito
- Faculty of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Hinako Yamamura
- Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan
| | - Takahide Kokumai
- Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan
| | - Akiko Furuya
- Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan
| | - Genya Taketazu
- Department of Pediatrics, Asahikawa Kosei General Hospital, Asahikawa, Japan
| | - Yoshio Makita
- Department of Genetic Counseling, Asahikawa Medical University Hospital, Asahikawa, Japan
| | - Yo Niida
- Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada, Japan
- Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan
| | - Satoru Takahashi
- Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan
| |
Collapse
|
2
|
Suzuki R, Sakakibara N, Murakami S, Ichikawa Y, Kitakado H, Ueda C, Tanaka Y, Okada E, Kondo A, Aoto Y, Ishiko S, Ishimori S, Nagano C, Yamamura T, Horinouchi T, Okamoto T, Nozu K. Genotype and X-chromosome inactivation are associated with disease severity in females with X-linked Alport syndrome. Nephrol Dial Transplant 2025; 40:688-695. [PMID: 39134512 DOI: 10.1093/ndt/gfae182] [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: 04/21/2024] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Male patients with X-linked Alport syndrome (XLAS) generally develop end-stage kidney disease in early or middle adulthood and show distinct genotype-phenotype correlations. However, female patients show various phenotypes ranging from asymptomatic to severe with no genotype-phenotype correlations. The factors affecting the severity of XLAS in female patients are unclear. Since X-chromosome inactivation (XCI) affects the severity of certain female X-linked diseases, we investigated whether genotype and XCI were associated with XLAS severity in female patients in a large Japanese cohort. METHODS Among 139 female patients with genetically diagnosed XLAS at our institution, we conducted XCI analysis on peripheral blood leucocytes using the human androgen receptor assay method and analysed two cohorts. In 74 adult female patients we evaluated the correlation between kidney function [creatinine estimated glomerular filtration rate (Cr-eGFR) optimized for Japanese individuals] and genotype/XCI using multivariable linear regression analysis and in 65 paediatric female patients we evaluated the correlation between kidney function (Cr-eGFR optimized for Japanese individuals) and genotype/XCI using multivariable linear regression analysis. We also investigated the correlation between the development of proteinuria (urine protein:creatinine ratio above normal for the patient's age) and genotype/XCI using multivariable Cox proportional hazards analysis. RESULTS In adult female patients, the XCI pattern was significantly associated with Cr-eGFR (regression coefficient estimate -0.53, P = .004), whereas genotype was not (P = .892). In paediatric female patients, both genotype and XCI pattern were significant independent risk factors for the development of proteinuria {hazard ratio [HR] 3.702 [95% confidence interval (CI) 1.681-8.150], P = .001 and HR 1.043 [95% CI 1.061-1.070], P = .001, respectively}, whereas both genotype and XCI pattern were not associated with Cr-eGFR (P = .20 and P = .67, respectively). CONCLUSION Genotype and XCI are factors associated with severity in females with XLAS.
Collapse
Affiliation(s)
- Ryota Suzuki
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
- Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Nana Sakakibara
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Sae Murakami
- Clinical and Translational Research Center, Kobe University Hospital , Kobe, Japan
| | - Yuta Ichikawa
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hideaki Kitakado
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Chika Ueda
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yu Tanaka
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Eri Okada
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Atsushi Kondo
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuya Aoto
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shinya Ishiko
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shingo Ishimori
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - China Nagano
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomohiko Yamamura
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomoko Horinouchi
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takayuki Okamoto
- Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan and
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|
3
|
Qin S, Luo Z, Wang J, Wang X, Chen X, Ye M, Leng X. Nephrogenic diabetes insipidus results from a novel in-frame deletion of AVPR2 gene in monozygotic-twin boys and their mother and grandmother. J Pediatr Endocrinol Metab 2025; 38:162-171. [PMID: 39648407 DOI: 10.1515/jpem-2024-0301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 11/21/2024] [Indexed: 12/10/2024]
Abstract
OBJECTIVES Mutations in the AVPR2 gene are the most common cause of nephrogenic diabetes insipidus (NDI). In-frame deletions of the AVPR2 gene are a rare variant that results in NDI. We report a novel variant of the p.H138del in an NDI family with twin male patients and three female carriers of different clinical phenotypes. METHODS The proband's blood genome was sequenced with a panel, and the variants were classified according to ACMG/AMP (2015) guidelines. X chromosome inactivation (XCI) was analyzed in the peripheral blood of his mother, grandmother, and maternal aunt, respectively. The haplotypes of the X chromosome were determined using their STR loci. RESULTS A novel in-frame deletion in the AVPR2 gene was detected in monozygotic-twin boys, and his mother, grandmother, and maternal aunt were heterozygous carriers. The two boys showed typical NDI, and their mother and grandmother presented polydipsia, polydipsia, and polyuria, but the maternal aunt did not have similar symptoms. The blood XCI results of the mother, grandmother, and maternal aunt showed random inactivation (36.18 , 48.37, and 49.30 %, respectively). The X haplotype indicated that the variant of the mother and grandmother was on their activated X chromosomes(Xa), while the maternal aunt's variant was on her inactivated X chromosome(Xi). CONCLUSIONS In-frame deletion of the AVPR2 gene within its functional domain can significantly affect protein function, which is one of the vital causes of NDI. The clinical variability of female carriers of AVPR2 is associated with underlying environmental and epigenetic factors or complex recombination of the X chromosomes.
Collapse
Affiliation(s)
- Shengfang Qin
- Department of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Women's and Children's Hospital/The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Zemin Luo
- Department of Internal Medicine and Paediatrics, Sichuan Provincial Women's and Children's Hospital/The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Jin Wang
- Department of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Women's and Children's Hospital/The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Xueyan Wang
- Department of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Women's and Children's Hospital/The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Ximin Chen
- Department of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Women's and Children's Hospital/The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Mengling Ye
- Department of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Women's and Children's Hospital/The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Xiangyou Leng
- Department of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Women's and Children's Hospital/The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| |
Collapse
|
4
|
Baek IC, Sim SY, Suh BK, Kim TG, Cho WK. Assessment of XCI skewing and demonstration of XCI escape region based on single-cell RNA sequencing: comparison between female Grave's disease and control. BMC Mol Cell Biol 2025; 26:8. [PMID: 39891056 PMCID: PMC11786500 DOI: 10.1186/s12860-025-00533-z] [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: 10/04/2024] [Accepted: 01/27/2025] [Indexed: 02/03/2025] Open
Abstract
BACKGROUND The reactivation and loss of mosaicism hypothesis due to X chromosome inactivation (XCI) skewing and escape could influence gender differences in autoimmune diseases. XCI selectively inactivates one of the two X chromosomes in females. METHODS To estimate XCI skewing and the occurrence of XCI escape, we conducted a normal female (NF) without a history of autoimmune thyroid disease (AITD) and a patient with Grave's disease (GD) based on a thyroid diagnosis. After single-cell RNA sequencing, heterozygous variants were converted and transformed. XCI skewing was calculated using the formula and the skewing degree was defined. NF/GD genes were compared using correction methods. Positions are heterozygous within a single cell as indicated by a unique barcode. RESULTS XCI skewing showed 45.8%/48.9% relatively random, 29.4%/27.0% skewing, 24.6%/23.7% severe skewing, and 0.2%/0.4% extreme severe skewing. 24.8%/24.1% in NF/GD exhibited severe skewing or higher. A total of 13 genes were significantly associated with XCI skewing ratios in NF/GD cells. In total, 371/250 nucleotide positions with only one barcode (representing a unique cell) were identified for XCI escape. A total of 143/52 nucleotide positions spanned 20/6 genes, and 12/1 genes were identified as XCI escapes. CONCLUSIONS These results could aid in understanding the immunogenetics of gender differences in various autoimmune disease pathophysiologies.
Collapse
Affiliation(s)
- In-Cheol Baek
- Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Soo Yeun Sim
- Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Byung-Kyu Suh
- Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Tai-Gyu Kim
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Won Kyoung Cho
- Department of Pediatrics, College of Medicine, St. Vincent's Hospital, The Catholic University of Korea, 93, Jungbu-daero, Paldal-gu, Suwon-si, Seoul, Gyeonggi-do, 16247, Republic of Korea.
| |
Collapse
|
5
|
Vaz D, Vasconcelos S, Caniçais C, Costa B, Ramalho C, Marques J, Dória S. X-chromosome inactivation pattern and telomere length in recurrent pregnancy loss. Reprod Biol 2024; 24:100933. [PMID: 39173315 DOI: 10.1016/j.repbio.2024.100933] [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: 03/23/2023] [Revised: 05/09/2024] [Accepted: 08/12/2024] [Indexed: 08/24/2024]
Abstract
Recurrent pregnancy loss is a reproductive disorder affecting about 1 to 5 % of pregnant women worldwide that requires our attention, especially considering that about 50 % of cases are idiopathic. The present study is focused on testing a possible association between extreme skewed X-chromosome inactivation patterns and/or shortened telomeres with idiopathic cases since both are considered non-consensual potential causes underlying recurrent pregnancy loss in the scientific community. For this purpose, two groups of women were analyzed and compared: a group of women with idiopathic recurrent pregnancy loss and a second group of age-matched women with proven fertility, and both X-chromosome inactivation patterns and telomere length were measured and compared from maternal DNA extracted from peripheral blood. Our data showed no statistically significant differences between groups, suggesting no association between extreme skewed X-chromosome inactivation or shortened telomeres with recurrent pregnancy losses. Additionally, the effect of maternal age on both X-chromosome inactivation pattern and telomere length was tested, but no significant correlation was observed between advanced maternal age and extreme skewed X-chromosome inactivation or telomere shortening. This study represents one more valid contribution to the investigation of causes underlying recurrent pregnancy loss suggesting that, new variables may be considered since the pattern of X-chromosome inactivation and telomere length do not seem to be related to this reproductive disorder. Briefly, considering its clinical relevance, it is mandatory a continuous effort in the scientific community to cover new potential recurrent pregnancy loss-related causes.
Collapse
Affiliation(s)
- Diane Vaz
- Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, Portugal.
| | - Sara Vasconcelos
- Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal.
| | - Carla Caniçais
- Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal.
| | - Beatriz Costa
- Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, Portugal.
| | - Carla Ramalho
- I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal; Department of Obstetrics and Gynecology, Centro Hospitalar São João and Faculty of Medicine, Porto, Portugal; Department of Gynecology-Obstetrics and Pediatrics, Faculty of Medicine, University of Porto, Portugal.
| | - Joana Marques
- Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal.
| | - Sofia Dória
- Genetics Unit, Department of Pathology, Faculty of Medicine, University of Porto, Portugal; I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal.
| |
Collapse
|
6
|
Gocuk SA, Lancaster J, Su S, Jolly JK, Edwards TL, Hickey DG, Ritchie ME, Blewitt ME, Ayton LN, Gouil Q. Measuring X-Chromosome inactivation skew for X-linked diseases with adaptive nanopore sequencing. Genome Res 2024; 34:1954-1965. [PMID: 39284686 PMCID: PMC11610576 DOI: 10.1101/gr.279396.124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 09/10/2024] [Indexed: 11/01/2024]
Abstract
X-linked genetic disorders typically affect females less severely than males owing to the presence of a second X Chromosome not carrying the deleterious variant. However, the phenotypic expression in females is highly variable, which may be explained by an allelic skew in X-Chromosome inactivation. Accurate measurement of X inactivation skew is crucial to understand and predict disease phenotype in carrier females, with prediction especially relevant for degenerative conditions. We propose a novel approach using nanopore sequencing to quantify skewed X inactivation accurately. By phasing sequence variants and methylation patterns, this single assay reveals the disease variant, X inactivation skew, and its directionality and is applicable to all patients and X-linked variants. Enrichment of X Chromosome reads through adaptive sampling enhances cost-efficiency. Our study includes a cohort of 16 X-linked variant carrier females affected by two X-linked inherited retinal diseases: choroideremia and RPGR-associated retinitis pigmentosa. As retinal DNA cannot be readily obtained, we instead determine the skew from peripheral samples (blood, saliva, and buccal mucosa) and correlate it to phenotypic outcomes. This reveals a strong correlation between X inactivation skew and disease presentation, confirming the value in performing this assay and its potential as a way to prioritize patients for early intervention, such as gene therapy currently in clinical trials for these conditions. Our method of assessing skewed X inactivation is applicable to all long-read genomic data sets, providing insights into disease risk and severity and aiding in the development of individualized strategies for X-linked variant carrier females.
Collapse
Affiliation(s)
- Sena A Gocuk
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville Victoria 3010, Australia
- Centre for Eye Research Australia, East Melbourne, Victoria 3002, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - James Lancaster
- Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
| | - Shian Su
- Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Jasleen K Jolly
- Vision and Eye Research Institute, Anglia Ruskin University, Cambridge CB1 2LZ, United Kingdom
| | - Thomas L Edwards
- Centre for Eye Research Australia, East Melbourne, Victoria 3002, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Doron G Hickey
- Centre for Eye Research Australia, East Melbourne, Victoria 3002, Australia
| | - Matthew E Ritchie
- Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Marnie E Blewitt
- Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Lauren N Ayton
- Department of Optometry and Vision Sciences, The University of Melbourne, Parkville Victoria 3010, Australia
- Centre for Eye Research Australia, East Melbourne, Victoria 3002, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, Victoria 3010, Australia
| | - Quentin Gouil
- Epigenetics and Development Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria 3010, Australia
| |
Collapse
|
7
|
Loges NT, Marthin JK, Raidt J, Olbrich H, Höben IM, Cindric S, Bracht D, König J, Rieck C, George S, Kloth TL, Wohlgemuth K, Pennekamp P, Dworniczak B, Holgersen MG, Römel J, Schmalstieg C, Aprea I, Mortensen J, Nielsen KG, Omran H. A range of 30-62% of functioning multiciliated airway cells is sufficient to maintain ciliary airway clearance. Eur Respir J 2024; 64:2301441. [PMID: 38991708 PMCID: PMC11469306 DOI: 10.1183/13993003.01441-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 06/16/2024] [Indexed: 07/13/2024]
Abstract
BACKGROUND Primary ciliary dyskinesia is a genetic disorder caused by aberrant motile cilia function that results in defective ciliary airway clearance and subsequently leads to recurrent airway infections and bronchiectasis. We aimed to determine: how many functional multiciliated airway cells are sufficient to maintain ciliary airway clearance? METHODS To answer this question we exploited the molecular defects of the X-linked recessive primary ciliary dyskinesia variant caused by pathogenic variants in DNAAF6 (PIH1D3), characterised by immotile cilia in affected males. We carefully analysed the clinical phenotype and molecular defect (using immunofluorescence and transmission electron microscopy) and performed in vitro studies (particle tracking in air-liquid interface cultures) and in vivo studies (radiolabelled tracer studies) to assess ciliary clearance of respiratory cells from female individuals with heterozygous and male individuals with hemizygous pathogenic DNAAF6 variants. RESULTS Primary ciliary dyskinesia male individuals with hemizygous pathogenic DNAAF6 variants displayed exclusively immotile cilia, absence of ciliary clearance and severe primary ciliary dyskinesia symptoms. Owing to random or skewed X-chromosome inactivation in six female carriers with heterozygous pathogenic DNAAF6 variants, 54.3±10% (range 38-70%) of multiciliated cells were defective. Nevertheless, in vitro and in vivo assessment of the ciliary airway clearance was normal or slightly abnormal. Consistently, heterozygous female individuals showed no or only mild respiratory symptoms. CONCLUSIONS Our findings indicate that having 30-62% of multiciliated respiratory cells functioning can generate either normal or slightly reduced ciliary clearance. Because heterozygous female carriers displayed either no or subtle respiratory symptoms, complete correction of 30% of cells by precision medicine could improve ciliary airway clearance in individuals with primary ciliary dyskinesia, as well as clinical symptoms.
Collapse
Affiliation(s)
- Niki T Loges
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - June Kehlet Marthin
- Danish PCD Centre, Danish Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Johanna Raidt
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Heike Olbrich
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Inga M Höben
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Sandra Cindric
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Diana Bracht
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Julia König
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Cynthia Rieck
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Sebastian George
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Tim Luis Kloth
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Kai Wohlgemuth
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Petra Pennekamp
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Bernd Dworniczak
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Mathias G Holgersen
- Danish PCD Centre, Danish Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jobst Römel
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christian Schmalstieg
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Isabella Aprea
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| | - Jann Mortensen
- Danish PCD Centre, Danish Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Kim G Nielsen
- Danish PCD Centre, Danish Paediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Heymut Omran
- Department of General Pediatrics, University Children's Hospital Muenster, Muenster, Germany
| |
Collapse
|
8
|
Cuinat S, Quélin C, Effray C, Dubourg C, Le Bouar G, Cabaret-Dufour AS, Loget P, Proisy M, Sauvestre F, Sarreau M, Martin-Berenguer S, Beneteau C, Naudion S, Michaud V, Arveiler B, Trimouille A, Macé P, Sigaudy S, Glazunova O, Torrents J, Raymond L, Saint-Frison MH, Attié-Bitach T, Lefebvre M, Capri Y, Bourgon N, Thauvin-Robinet C, Tran Mau-Them F, Bruel AL, Vitobello A, Denommé-Pichon AS, Faivre L, Brehin AC, Goldenberg A, Patrier-Sallebert S, Perani A, Dauriat B, Bourthoumieu S, Yardin C, Marquet V, Barnique M, Fiorenza-Gasq M, Marey I, Tournadre D, Doumit R, Nugues F, Barakat TS, Bustos F, Jaillard S, Launay E, Pasquier L, Odent S. Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective. J Med Genet 2024; 61:824-832. [PMID: 38849204 PMCID: PMC11420740 DOI: 10.1136/jmg-2024-109854] [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: 01/05/2024] [Accepted: 05/19/2024] [Indexed: 06/09/2024]
Abstract
INTRODUCTION Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described. METHOD After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases. RESULTS We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots. CONCLUSION Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.
Collapse
Affiliation(s)
- Silvestre Cuinat
- Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CHU Rennes, Rennes, France
| | - Chloé Quélin
- Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CHU Rennes, Rennes, France
- Service d'Anatomie et Cytologie Pathologiques, Hôpital Pontchaillou, CHU Rennes, Rennes, France
| | - Claire Effray
- Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CHU Rennes, Rennes, France
| | - Christèle Dubourg
- Laboratoire de Génétique Moléculaire, Hôpital Pontchaillou, CHU Rennes, Rennes, France
- CNRS, INSERM UMR 6290, ERL U1305, F-35000, Université de Rennes, IGDR, Rennes, France
| | - Gwenaelle Le Bouar
- Unité de Médecine fœtale, Service de Gynécologie-Obstétrique, CHU Rennes, Rennes, France
| | | | - Philippe Loget
- Service d'Anatomie et Cytologie Pathologiques, Hôpital Pontchaillou, CHU Rennes, Rennes, France
| | - Maia Proisy
- Radiology Department, CHU de Brest, Brest, France
| | - Fanny Sauvestre
- Unité de Pathologie Fœto-placentaire, Service de Pathologie, CHU de Bordeaux, Bordeaux, France
| | - Mélie Sarreau
- Unité de Pathologie Fœto-placentaire, Service de Pathologie, CHU de Bordeaux, Bordeaux, France
| | - Sophie Martin-Berenguer
- Unité de Pathologie Fœto-placentaire, Service de Pathologie, CHU de Bordeaux, Bordeaux, France
- Department of Gynaecology and Obstetrics, Mother and Children's Hospital, CHU Limoges, Limoges, France
| | - Claire Beneteau
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
| | - Sophie Naudion
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
| | - Vincent Michaud
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
- INSERM U1211, Maladies Rares, Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
| | - Benoit Arveiler
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
- INSERM U1211, Maladies Rares, Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
| | - Aurélien Trimouille
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
- INSERM U1211, Maladies Rares, Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
| | - Pierre Macé
- Institut méditerranéen d'imagerie médicale appliquée à la gynécologie, la grossesse et l'enfance IMAGE2, Marseille, France
| | - Sabine Sigaudy
- Département de Génétique Médicale, Hôpital Timone Enfant, AP-HM, Marseille, France
| | - Olga Glazunova
- Département de Génétique Médicale, Hôpital Timone Enfant, AP-HM, Marseille, France
| | - Julia Torrents
- Department of Pathology and Neuropathology, La Timone Hospital, Aix Marseille University, AP-HM, Marseille, France
| | - Laure Raymond
- Genetics Department, Laboratoire Eurofins Biomnis, Lyon, France
| | | | - Tania Attié-Bitach
- Service de Médecine Génomique des Maladies Rares, Hopital Universitaire Necker-Enfants Malades, AP-HP, Paris, France
- INSERM UMR 1163, Imagine Institute, Université Paris Cité, Paris, France
| | - Mathilde Lefebvre
- Service de Pathologie fœtale, Hôpital Universitaire Armand Trousseau, AP-HP, Paris, France
| | - Yline Capri
- Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France
| | - Nicolas Bourgon
- Service d'Obstétrique-Maternité Chirurgie, Médecine et Imagerie foetales, AP-HP, Hopital Universitaire Necker-Enfants Malades, Paris, France
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
| | - Christel Thauvin-Robinet
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon, Dijon, France
- Centre de référence Anomalies du Développement et Syndromes Malformatifs, Fédération Hospitalo-Universitaire TRANSLAD, CHU Dijon, Dijon, France
| | - Frédéric Tran Mau-Them
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon, Dijon, France
| | - Ange-Line Bruel
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon, Dijon, France
| | - Antonio Vitobello
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon, Dijon, France
| | - Anne-Sophie Denommé-Pichon
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon, Dijon, France
| | - Laurence Faivre
- UMR1231 GAD, INSERM, Université Bourgogne Franche-Comté, Dijon, France
- Centre de référence Anomalies du Développement et Syndromes Malformatifs, Fédération Hospitalo-Universitaire TRANSLAD, CHU Dijon, Dijon, France
| | - Anne-Claire Brehin
- Department of Pathology, Department of Genetics and Reference Center for Developmental Abnormalities, F-76000, CHU de Rouen, Rouen, France
- Inserm U1245, Université de Rouen Normandie, Rouen, France
| | - Alice Goldenberg
- Inserm U1245, Université de Rouen Normandie, Rouen, France
- Department of Genetics and Reference Center for Developmental Abnormalities, F-76000, CHU de Rouen, Rouen, France
| | | | - Alexandre Perani
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
| | - Benjamin Dauriat
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
| | - Sylvie Bourthoumieu
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
- UMR 7252, CNRS, XLIM, F-87000, Université de Limoges, Limoges, France
| | - Catherine Yardin
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
- UMR 7252, CNRS, XLIM, F-87000, Université de Limoges, Limoges, France
| | - Valentine Marquet
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
| | - Marion Barnique
- Cytogenetic, Medical Genetic and Reproductive Biology Department, Hôpital de la Mère et de l'Enfant, CHU Dupuytren, CHU Limoges, Limoges, France
| | - Maryse Fiorenza-Gasq
- Department of Gynaecology and Obstetrics, Mother and Children's Hospital, CHU Limoges, Limoges, France
| | - Isabelle Marey
- INSERM U1209, Institute for Advanced Bioscience, Université Grenoble Alpes, Grenoble, France
| | - Danielle Tournadre
- CPDPN de Grenoble, Echographie obstétricale dépistage et diagnostic, CHU Grenoble Alpes, Grenoble, France
| | - Raïa Doumit
- Service d'Imagerie Pédiatrique, CHU Grenoble Alpes, Grenoble, France
| | - Frédérique Nugues
- Service d'Imagerie Pédiatrique, CHU Grenoble Alpes, Grenoble, France
| | - Tahsin Stefan Barakat
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, Rotterdam, The Netherlands
- Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Francisco Bustos
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, South Dakota, USA
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA
| | - Sylvie Jaillard
- Service de Cytogénétique et Biologie Cellulaire, CHU Rennes, Rennes, France
- EHESP, INSERM U1085 IRSET, Université de Rennes 1, Rennes, France
| | - Erika Launay
- Service de Cytogénétique et Biologie Cellulaire, CHU Rennes, Rennes, France
| | - Laurent Pasquier
- Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CHU Rennes, Rennes, France
- CNRS, INSERM UMR 6290, ERL U1305, F-35000, Université de Rennes, IGDR, Rennes, France
- FHU GenoMeds, ERN ITHACA, CHU Rennes, Rennes, France
| | - Sylvie Odent
- Service de Génétique Clinique, CRMR anomalies du développement CLAD-Ouest, CHU Rennes, Rennes, France
- CNRS, INSERM UMR 6290, ERL U1305, F-35000, Université de Rennes, IGDR, Rennes, France
- FHU GenoMeds, ERN ITHACA, CHU Rennes, Rennes, France
| |
Collapse
|
9
|
Lombardo A, Sinibaldi L, Genovese S, Catino G, Mei V, Pompili D, Sallicandro E, Falasca R, Liambo MT, Faggiano MV, Roberti MC, Di Donato M, Vitelli A, Russo S, Giannini R, Micalizzi A, Pietrafusa N, Digilio MC, Novelli A, Fusco L, Alesi V. A Case of CDKL5 Deficiency Due to an X Chromosome Pericentric Inversion: Delineation of Structural Rearrangements as an Overlooked Recurrent Pathological Mechanism. Int J Mol Sci 2024; 25:6912. [PMID: 39000022 PMCID: PMC11241409 DOI: 10.3390/ijms25136912] [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: 05/07/2024] [Revised: 06/11/2024] [Accepted: 06/13/2024] [Indexed: 07/14/2024] Open
Abstract
CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic variants inactivating CDKL5 or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) the standard diagnostic tests. We report a suspicious case of CDD in a female child who tested negative upon NGS and CMA and harbored an X chromosome de novo pericentric inversion. The use of recently developed genomic techniques (optical genome mapping and whole-genome sequencing) allowed us to finely characterize the breakpoints, with one of them interrupting CDKL5 at intron 1. This is the fifth case of CDD reported in the scientific literature harboring a structural rearrangement on the X chromosome, providing evidence for the hypothesis that this type of anomaly can represent a recurrent pathogenic mechanism, whose frequency is likely underestimated, with it being overlooked by standard techniques. The identification of the molecular etiology of the disorder is extremely important in evaluating the pathological outcome and to better investigate the mechanisms associated with drug resistance, paving the way for the development of specific therapies. Karyotype and genomic techniques should be considered in all cases presenting with CDD without molecular confirmation.
Collapse
Affiliation(s)
- Antonietta Lombardo
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Lorenzo Sinibaldi
- Medical Genetics Unit, IRCCS Bambino Gesù Children Hospital, 00165 Rome, Italy
| | - Silvia Genovese
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Giorgia Catino
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Valerio Mei
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Daniele Pompili
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Ester Sallicandro
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Roberto Falasca
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Maria Teresa Liambo
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Maria Vittoria Faggiano
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Maria Cristina Roberti
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Maddalena Di Donato
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Anna Vitelli
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Serena Russo
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Rosalinda Giannini
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Alessia Micalizzi
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
- Medical Genetics Unit, San Pietro Fatebenefratelli Hospital, 00189 Rome, Italy
| | - Nicola Pietrafusa
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù, IRCCS Children’s Hospital, 00165 Rome, Italy
| | | | - Antonio Novelli
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| | - Lucia Fusco
- Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù, IRCCS Children’s Hospital, 00165 Rome, Italy
| | - Viola Alesi
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
| |
Collapse
|
10
|
Di H, Wang Q, Liang D, Zhang J, Gao E, Zheng C, Yu X, Liu Z. Genetic features and kidney morphological changes in women with X-linked Alport syndrome. J Med Genet 2023; 60:1169-1176. [PMID: 37225412 DOI: 10.1136/jmg-2023-109221] [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: 02/15/2023] [Accepted: 05/10/2023] [Indexed: 05/26/2023]
Abstract
BACKGROUND X-linked Alport syndrome (XLAS) caused by COL4A5 pathogenic variants usually has heterogeneous phenotypes in female patients. The genetic characteristics and glomerular basement membrane (GBM) morphological changes in women with XLAS need to been further investigated. METHODS A total of 83 women and 187 men with causative COL4A5 variants were enrolled for comparative analysis. RESULTS Women were more frequently carrying de novo COL4A5 variants compared with men (47% vs 8%, p=0.001). The clinical manifestations in women were variable, and no genotype-phenotype correlation was observed. Coinherited podocyte-related genes, including TRPC6, TBC1D8B, INF2 and MYH9, were identified in two women and five men, and the modifying effects of coinherited genes contributed to the heterogeneous phenotypes in these patients. X-chromosome inactivation (XCI) analysis of 16 women showed that 25% were skewed XCI. One patient preferentially expressing the mutant COL4A5 gene developed moderate proteinuria, and two patients preferentially expressing the wild-type COL4A5 gene presented with haematuria only. GBM ultrastructural evaluation demonstrated that the degree of GBM lesions was associated with the decline in kidney function for both genders, but more severe GBM changes were found in men compared with women. CONCLUSIONS The high frequency of de novo variants carried by women indicates that the lack of family history tends to make them susceptible to be underdiagnosed. Coinherited podocyte-related genes are potential contributors to the heterogeneous phenotype of some women. Furthermore, the association between the degree of GBM lesions and decline in kidney function is valuable in evaluating the prognosis for patients with XLAS.
Collapse
Affiliation(s)
- Hongling Di
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Qing Wang
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
- Department of Nephrology, General Hospital of Eastern Theater Command, Naval Medical University, Shanghai, Shanghai, China
| | - Dandan Liang
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Jiahui Zhang
- The Key Laboratory of Biosystems Homeostasis & Protection of Ministry of Education, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Erzhi Gao
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Chunxia Zheng
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Xiaomin Yu
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| |
Collapse
|
11
|
Mou W, Zhao Z, Gao L, Fu L, Li J, Jiao A, Peng Y, Yu T, Guo Y, Chen L, Wang H, Liu J, Qin Q, Xu B, Liu X, He J, Gui J. An Atypical Incontinentia Pigmenti Female with Persistent Mucocutaneous Hyperinflammation and Immunodeficiency Caused by a Novel Germline IKBKG Missense Mutation. J Clin Immunol 2023; 43:2165-2180. [PMID: 37831401 DOI: 10.1007/s10875-023-01564-x] [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: 11/15/2022] [Accepted: 08/02/2023] [Indexed: 10/14/2023]
Abstract
While most missense mutations of the IKBKG gene typically result in Ectodermal Dysplasia with Immunodeficiency, there have been rare reported instances of missense mutations of the IKBKG gene causing both Incontinentia Pigmenti (IP) and immunodeficiency in female patients. In this study, we described an atypical IP case in a 19-year-old girl, characterized by hyperpigmented and verrucous skin areas over the entire body. Remarkably, she experienced recurrent red papules whenever she had a feverish upper respiratory tract infection. Immunohistochemical staining unveiled a substantial accumulation of CD68+ macrophages alongside the TNF-α positive cells in the dermis tissue of new pustules, with increased apoptotic basal keratinocytes in the epidermis tissue of these lesions. Starting from the age of 8 years old, the patient suffered from severe and sustained chronic respiratory mucous membrane scar hyperplasia and occluded subglottic lumen. In addition to elevated erythrocyte sedimentation rate values, inflammatory cells were observed in the pathologic lesions of endobronchial biopsies and Bronchoalveolar Lavage Fluid (BALF) smear. Further histological analysis revealed a destructive bronchus epithelium integrity with extensive necrosis. Simultaneously, the patient experienced recurrent incomplete intestinal obstructions and lips contracture. The patient's BALF sample displayed an augmented profile of proinflammatory cytokines and chemokines, suggesting a potential link to systemic hyperinflammation, possibly underlying the pathogenic injuries affecting the subglottic, respiratory, and digestive systems. Furthermore, the patient presented with recurrent pneumonias and multiple warts accompanied by a T+BlowNKlow immunophenotype. Next generation sequencing showed that the patient carried a novel de novo germline heterozygous missense mutation in the IKBKG gene (c. 821T>C, p. L274P), located in the highly conserved CC2 domain. TA-cloning sequencing of patient's cDNA yielded 30 mutant transcripts out of 44 clones. In silico analysis indicated that the hydrogen bond present between Ala270 and Leu274 in the wild-type NEMO was disrupted by the Leu274Pro mutation. However, this mutation did not affect NEMO expression in peripheral blood mononuclear cells (PBMCs). Moreover, patient PBMCs exhibited significantly impaired TNF-α production following Lipopolysaccharide (LPS) stimulation. X-chromosome inactivation in T cells and neutrophils were not severely skewed. Reduced levels of IκBα phosphorylation and degradation in patient's PBMCs were observed. The NF-κB luciferase reporter assay conducted using IKBKG-deficient HEK293T cells revealed a significant reduction in NF-kB activity upon LPS stimulation. These findings adds to the ever-growing knowledge on female IP that might contribute to the better understanding of this challenging disorder.
Collapse
Affiliation(s)
- Wenjun Mou
- Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Zhipeng Zhao
- Department of Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China
| | - Liwei Gao
- Department of Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China
| | - Libing Fu
- Department of Pathology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Jia Li
- Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Anxia Jiao
- Department of Interventional Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China
| | - Yun Peng
- Department of Radiology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Tong Yu
- Department of Radiology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China
| | - Yan Guo
- Department of Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China
| | - Lanqin Chen
- Department of Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China
| | - Hao Wang
- Department of Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China
| | - Jun Liu
- Department of Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China
| | - Qiang Qin
- Department of Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China
| | - Baoping Xu
- Department of Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China
| | - Xiuyun Liu
- Department of Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China.
| | - Jianxin He
- Department of Pulmonology, Beijing Children's Hospital, Capital Medical University, National Clinical Research Center of Respiratory Diseases, National Center for Children's Health, Beijing, 100045, China.
| | - Jingang Gui
- Laboratory of Tumor Immunology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China.
| |
Collapse
|
12
|
de Carvalho Kimura T, de Lima-Souza RA, Scarini JF, Lavareze L, Egal ESA, Altemani A, Mariano FV. Clinicopathological profile of sclerosing polycystic adenoma/adenosis: A systematic review. Head Neck 2023; 45:2449-2457. [PMID: 37403748 DOI: 10.1002/hed.27435] [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: 03/27/2023] [Revised: 05/10/2023] [Accepted: 06/09/2023] [Indexed: 07/06/2023] Open
Abstract
In this systematic review, we aimed to evaluate the clinicopathological profile of sclerosing polycystic adenoma (SPA). PubMed, Scopus, EMBASE, Lilacs, Web of Science, and gray literature were searched to access cases of SPA in salivary glands. One hundred and thirty cases of SPA were found across 61 selected articles. SPA affected mainly the parotid gland of adults with a mean age of 44.6 years old, with a slight preference for females. The lesion was usually presented as a painless firm mass with a long period of evolution. Histologically, they are well-delimitated lesions composed of acinar and ductal elements with a variety of cytomorphologic features surrounded by a densely collagenized stroma. PI3K was the most common gene mutation related to SPA. SPA is a benign condition that mainly affects the parotid gland of female patients and it is usually treated by surgical resection with a good prognosis.
Collapse
Affiliation(s)
- Talita de Carvalho Kimura
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, Brazil
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil
| | - Reydson Alcides de Lima-Souza
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, Brazil
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil
| | - João Figueira Scarini
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, Brazil
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil
| | - Luccas Lavareze
- Department of Oral Diagnosis, Piracicaba Dental School, State University of Campinas (UNICAMP), Piracicaba, Brazil
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil
| | - Erika Said Abu Egal
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil
- Biorepository and Molecular Pathology, Huntsman Cancer Institute, University of Utah (UU), Salt Lake City, Utah, USA
| | - Albina Altemani
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil
| | - Fernanda Viviane Mariano
- Department of Pathology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil
| |
Collapse
|
13
|
Gocuk SA, Jolly JK, Edwards TL, Ayton LN. Female carriers of X-linked inherited retinal diseases - Genetics, diagnosis, and potential therapies. Prog Retin Eye Res 2023; 96:101190. [PMID: 37406879 DOI: 10.1016/j.preteyeres.2023.101190] [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: 03/09/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 07/07/2023]
Abstract
Inherited retinal diseases (IRDs) are a group of heterogeneous conditions that cause progressive vision loss, typically due to monogenic mutations. Female carriers of X-linked IRDs have a single copy of the disease-causing gene, and therefore, may exhibit variable clinical signs that vary from near normal retina to severe disease and vision loss. The relationships between individual genetic mutations and disease severity in X-linked carriers requires further study. This review summarises the current literature surrounding the spectrum of disease seen in female carriers of choroideremia and X-linked retinitis pigmentosa. Various classification systems are contrasted to accurately grade retinal disease. Furthermore, genetic mechanisms at the early embryonic stage are explored to potentially explain the variability of disease seen in female carriers. Future research in this area will provide insight into the association between genotype and retinal phenotypes of female carriers, which will guide in the management of these patients. This review acknowledges the importance of identifying which patients may be at high risk of developing severe symptoms, and therefore should be considered for emerging treatments, such as retinal gene therapy.
Collapse
Affiliation(s)
- Sena A Gocuk
- Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Victoria, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia; Ophthalmology, Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia
| | - Jasleen K Jolly
- Vision and Eye Research Institute, Anglia Ruskin University, Cambridge, UK
| | - Thomas L Edwards
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia; Ophthalmology, Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia
| | - Lauren N Ayton
- Department of Optometry and Vision Sciences, The University of Melbourne, Melbourne, Victoria, Australia; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia; Ophthalmology, Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia.
| |
Collapse
|
14
|
Buono MF, Benavente ED, Daniels M, Mol BM, Mekke JM, de Borst GJ, de Kleijn DPV, van der Laan SW, Pasterkamp G, Onland-Moret C, Mokry M, den Ruijter HM. X chromosome inactivation skewing is common in advanced carotid atherosclerotic lesions in females and predicts secondary peripheral artery events. Biol Sex Differ 2023; 14:43. [PMID: 37408072 PMCID: PMC10324263 DOI: 10.1186/s13293-023-00527-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 06/24/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND AND AIM Sex differences in atherosclerosis have been described with female plaques being mostly perceived as stable and fibrous. Sex-specific mechanisms such as mosaic loss of the Y chromosome in men have been linked to cardiovascular health. In women, X-linked mechanisms such as X chromosome inactivation (XCI) skewing is common in several tissues. Yet, information on the role of XCI in female atherosclerotic plaques is lacking. Here, we investigated the presence of XCI skewing in advanced atherosclerotic lesions and its association with cardiovascular risk factors, histological plaque data, and clinical data. METHODS XCI skewing was quantified in 154 atherosclerotic plaque and 55 blood DNA samples of women included in the Athero-Express study. The skewing status was determined performing the HUMARA assay. Then, we studied the relationship of XCI skewing in female plaque and cardiovascular risk factors using regression models. In addition, we studied if plaque XCI predicted plaque composition, and adverse events during 3-years follow-up using Cox proportional hazard models. RESULTS XCI skewing was detected in 76 of 154 (49.4%) plaques and in 27 of 55 (67%) blood samples. None of the clinical risk factors were associated with plaque skewing. Plaque skewing was more often detected in plaques with a plaque hemorrhage (OR [95% CI]: 1.44 [1.06-1.98], P = 0.02). Moreover, skewed plaques were not associated with a higher incidence of composite and major events but were specifically associated with peripheral artery events during a 3-year follow-up period in a multivariate model (HR [95%CI]: 1.46 [1.09-1.97]; P = 0.007). CONCLUSIONS XCI skewing is common in carotid plaques of females and is predictive for the occurrence of peripheral artery events within 3 years after carotid endarterectomy.
Collapse
Affiliation(s)
- Michele F Buono
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Ernest Diez Benavente
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Mark Daniels
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Barend M Mol
- Department of Vascular Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Joost M Mekke
- Department of Vascular Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Gert J de Borst
- Department of Vascular Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Dominique P V de Kleijn
- Department of Vascular Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Sander W van der Laan
- Central Diagnostics Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Gerard Pasterkamp
- Central Diagnostics Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Charlotte Onland-Moret
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Michal Mokry
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Central Diagnostics Laboratory, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Hester M den Ruijter
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
| |
Collapse
|
15
|
Minić S, Cerovac N, Novaković I, Gazikalović S, Popadić S, Trpinac D. The Impact of the IKBKG Gene on the Appearance of the Corpus Callosum Abnormalities in Incontinentia Pigmenti. Diagnostics (Basel) 2023; 13:diagnostics13071300. [PMID: 37046518 PMCID: PMC10093331 DOI: 10.3390/diagnostics13071300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/19/2023] [Accepted: 03/28/2023] [Indexed: 03/31/2023] Open
Abstract
Incontinentia pigmenti (IP) is a rare skin disease combined with anomalies of the teeth, eyes, and central nervous system (CNS). Mutations of the IKBKG gene are responsible for IP. Among the most frequent CNS abnormalities found in IP using magnetic resonance imaging (MRI) are corpus callosum (CC) abnormalities. The aim of the study was to determine the presence of CC abnormalities, their relationship with the IKBKG mutations, and the possible presence of mutations of other genes. A group of seven IP patients was examined. Analyses of the IKBKG gene and the X-chromosome inactivation pattern were performed, as well as MRI and whole exome sequencing (WES) with the focus on the genes relevant for neurodegeneration. WES analysis showed IKBKG mutation in all examined patients. A patient who had a mutation of a gene other than IKBKG was excluded from further study. Four of the seven patients had clinically diagnosed CNS anomalies; two out of four had MRI-diagnosed CC anomalies. The simultaneous presence of IKBKG mutation and CC abnormalities and the absence of other mutations indicate that IKBKG may be the cause of CC abnormalities and should be included in the list of genes responsible for CC abnormalities.
Collapse
|
16
|
Iannuzzi V, Bacalini MG, Franceschi C, Giuliani C. The role of genetics and epigenetics in sex differences in human survival. GENUS 2023. [DOI: 10.1186/s41118-023-00181-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
AbstractSex differences in human survival have been extensively investigated in many studies that have in part uncovered the biological determinants that promote a longer life in females with respect to males. Moreover, researches performed in the past years have prompted increased awareness about the biological effects of environmental factors that can modulate the magnitude of the sex gap in survival. Besides the genetic background, epigenetic modifications like DNA methylation, that can modulate cell function, have been particularly studied in this framework. In this review, we aim to summarize the role of the genetic and epigenetic mechanisms in promoting female advantage from the early in life (“INNATE” features), and in influencing the magnitude of the gap in sex differences in survival and ageing (“VARIABLE” features). After briefly discussing the biological bases of sex determination in humans, we will provide much evidence showing that (i) “innate” mechanisms common to all males and to all females (both genetic and epigenetic) play a major role in sex differences in lifespan; (ii) “variable” genetic and epigenetic patterns, that vary according to context, populations and exposures to different environments, can affect the magnitude of the gap in sex differences in survival. Then we will describe recent findings in the use of epigenetic clocks to uncover sex differences in biological age and thus potentially in mortality. In conclusion, we will discuss how environmental factors cannot be kept apart from the biological factors providing evidence from the field of human ecology.
Collapse
|
17
|
Li Q, Chen S, Dong X, Fu S, Zhang T, Zheng W, Tian Y, Huang D. The Progress of Research on Genetic Factors of Recurrent Pregnancy Loss. Genet Res (Camb) 2023; 2023:9164374. [PMID: 37006462 PMCID: PMC10065863 DOI: 10.1155/2023/9164374] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 02/09/2023] [Accepted: 02/16/2023] [Indexed: 04/04/2023] Open
Abstract
Recurrent pregnancy loss (RPL) is both mental and physical health problem affecting about 1-5% of women of childbearing age. The etiology of RPL is complex, involving chromosomal abnormalities, autoimmune diseases, metabolic disorders, and endometrial dysfunction. The causes of abortion are still unknown in more than 50% of these cases. With the development of science and technology, an increasing number of scholars focus on this field and find that genetic factors may play an essential role in unexplained RPL, such as embolism-related genes, immune factor-related genes, and chromosomal numeric, and structural variation. This review summarizes the genetic factors associated with RPL, including genetic mutations and genetic polymorphisms, chromosomal variants, and chromosomal polymorphisms. Many related genetic factors have been found to be demographically and geographically relevant, some of which can be used for risk prediction or screening for the etiology of RPL. However, it is difficult to predict and prevent RPL due to uncertain pathogenesis and highly variable clinical presentation. Therefore, the genetic factors of RPL still need plentiful research to obtain a more accurate understanding of its pathogenesis and to provide more detection means for the screening and prevention of RPL.
Collapse
Affiliation(s)
- Qinlan Li
- Institute of Reproduction Health Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Shuting Chen
- Institute of Reproduction Health Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Xinyi Dong
- Institute of Reproduction Health Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Sen Fu
- Institute of Reproduction Health Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Tianyu Zhang
- Institute of Reproduction Health Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Weiwei Zheng
- NHC Key Laboratory of Male Reproduction and Genetics (Family Planning Research Institute of Guangdong Province), Guangzhou 510600, Guangdong, China
| | - Yonghong Tian
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang, China
| | - Donghui Huang
- Institute of Reproduction Health Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| |
Collapse
|
18
|
Juchniewicz P, Kloska A, Portalska K, Jakóbkiewicz-Banecka J, Węgrzyn G, Liss J, Głodek P, Tukaj S, Piotrowska E. X-chromosome inactivation patterns depend on age and tissue but not conception method in humans. Chromosome Res 2023; 31:4. [PMID: 36695960 PMCID: PMC9877087 DOI: 10.1007/s10577-023-09717-9] [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: 09/16/2022] [Revised: 11/27/2022] [Accepted: 12/06/2022] [Indexed: 01/26/2023]
Abstract
Female somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes, randomly silencing the maternal or paternal X chromosome in each cell of 46,XX females. Skewed XCI toward one parental X has been observed in association with ageing and in some female carriers of X-linked diseases. To address the problem of non-random XCI, we quantified the XCI skew in different biological samples of naturally conceived females of different age groups and girls conceived after in vitro fertilization (IVF). Generally, XCI skew differed between saliva, blood, and buccal swabs, while saliva and blood had the most similar XCI patterns in individual females. XCI skew increased with age in saliva, but not in other tissues. We showed no significant differences in the XCI patterns in tissues of naturally conceived and IVF females. The gene expression profile of the placenta and umbilical cord blood was determined depending on the XCI pattern. The increased XCI skewing in the placental tissue was associated with the differential expression of several genes out of 40 considered herein. Notably, skewed XCI patterns (> 80:20) were identified with significantly increased expression levels of four genes: CD44, KDM6A, PHLDA2, and ZRSR2. The differences in gene expression patterns between samples with random and non-random XCI may shed new light on factors contributing to the XCI pattern outcome and indicate new paths in future research on the phenomenon of XCI skewing.
Collapse
Affiliation(s)
- Patrycja Juchniewicz
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
| | - Anna Kloska
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
| | - Karolina Portalska
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
| | - Joanna Jakóbkiewicz-Banecka
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
| | - Grzegorz Węgrzyn
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
| | - Joanna Liss
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland ,Research and Development Center, INVICTA, Sopot, Poland
| | - Piotr Głodek
- Research and Development Center, INVICTA, Sopot, Poland
| | - Stefan Tukaj
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
| | - Ewa Piotrowska
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland
| |
Collapse
|
19
|
Günthner R, Knipping L, Jeruschke S, Satanoskij R, Lorenz-Depiereux B, Hemmer C, Braunisch MC, Riedhammer KM, Ćomić J, Tönshoff B, Tasic V, Abazi-Emini N, Nushi-Stavileci V, Buiting K, Gjorgjievski N, Momirovska A, Patzer L, Kirschstein M, Gross O, Lungu A, Weber S, Renders L, Heemann U, Meitinger T, Büscher AK, Hoefele J. Renal X-inactivation in female individuals with X-linked Alport syndrome primarily determined by age. Front Med (Lausanne) 2022; 9:953643. [PMID: 36341250 PMCID: PMC9630586 DOI: 10.3389/fmed.2022.953643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 09/21/2022] [Indexed: 08/29/2023] Open
Abstract
X-linked Alport syndrome (AS) caused by hemizygous disease-causing variants in COL4A5 primarily affects males. Females with a heterozygous state show a diverse phenotypic spectrum ranging from microscopic hematuria to end-stage kidney disease (ESKD) and extrarenal manifestations. In other X-linked diseases, skewed X-inactivation leads to preferential silencing of one X-chromosome and thus can determine the phenotype in females. We aimed to show a correlation between X-inactivation in blood and urine-derived renal cells and clinical phenotype of females with a heterozygous disease-causing variant in COL4A5 compared to healthy controls. A total of 56 females with a heterozygous disease-causing COL4A5 variant and a mean age of 31.6 ± 18.3 SD years were included in this study. A total of 94% had hematuria, 62% proteinuria >200 mg/day, yet only 7% had decreased eGFR. Using human androgen receptor assay X-inactivation was examined in blood cells of all 56 individuals, in urine-derived cells of 27 of these individuals and in all healthy controls. X-inactivation did not correlate with age of first manifestation, proteinuria or eGFR neither in blood, nor in urine. The degree of X-inactivation showed a moderate association with age, especially in urine-derived cells of the patient cohort (rho = 0.403, p = 0.037). Determination of X-inactivation allelity revealed a shift of X-inactivation toward the COL4A5 variant bearing allele. This is the first study examining X-inactivation of urine-derived cells from female individuals with AS. A correlation between phenotype and X-inactivation could not be observed suspecting other genetic modifiers shaping the phenotype in female individuals with AS. The association of X-inactivation with age in urine-derived cells suggests an escape-mechanism inactivating the COL4A5 variant carrying allele in female individuals with AS.
Collapse
Affiliation(s)
- Roman Günthner
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Lea Knipping
- Pediatric Nephrology, University Hospital Essen, Essen, Germany
| | | | - Robin Satanoskij
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | | | - Clara Hemmer
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Matthias C. Braunisch
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Korbinian M. Riedhammer
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Jasmina Ćomić
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Burkhard Tönshoff
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Velibor Tasic
- University Children’s Hospital, Medical Faculty of Skopje, Skopje, North Macedonia
| | - Nora Abazi-Emini
- University Children’s Hospital, Medical Faculty of Skopje, Skopje, North Macedonia
| | | | - Karin Buiting
- Institute for Human Genetics, University Hospital Essen, Essen, Germany
| | - Nikola Gjorgjievski
- University Hospital of Nephrology, Faculty of Medicine, University “Ss Cyril and Methodius,” Skopje, North Macedonia
| | | | - Ludwig Patzer
- Department of Pediatrics, Children’s Hospital St. Elisabeth and St. Barbara, Halle (Saale), Germany
| | | | - Oliver Gross
- Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany
| | - Adrian Lungu
- Fundeni Clinical Institute, Pediatric Nephrology Department, Bucharest, Romania
| | - Stefanie Weber
- Department of Pediatrics II, University Children’s Hospital, Philipps-University Marburg, Marburg, Germany
| | - Lutz Renders
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Uwe Heemann
- Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Thomas Meitinger
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Anja K. Büscher
- Pediatric Nephrology, University Hospital Essen, Essen, Germany
| | - Julia Hoefele
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| |
Collapse
|
20
|
Liu H, Su L, Liu H, Zheng J, Feng H, Liu Y, Yu M, Han D. Rare X-Linked Hypohidrotic Ectodermal Dysplasia in Females Associated with Ectodysplasin-A Variants and the X-Chromosome Inactivation Pattern. Diagnostics (Basel) 2022; 12:diagnostics12102300. [PMID: 36291989 PMCID: PMC9600026 DOI: 10.3390/diagnostics12102300] [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: 09/05/2022] [Revised: 09/18/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
The goal of this study was to identify the pathogenic gene variants in female patients with severe X-linked hypohidrotic ectodermal dysplasia (XLHED). Whole-exome sequencing (WES) and Sanger sequencing were used to screen for the pathogenic gene variants. The harmfulness of these variations was predicted by bioinformatics. Then, skewed X-chromosome inactivation (XCI) was measured by PCR analysis of the CAG repeat region in the human androgen receptor (AR) gene in peripheral blood cells. Two novel Ectodysplasin-A (EDA) heterozygous variants (c.588_606del19bp and c.837G>A) and one heterozygous variant (c.1045G>A, rs132630317) were identified in the three female XLHED patients. The bioinformatics analysis showed that these variants might be pathogenic. The tertiary structure analysis showed that these variants could cause structural damage to EDA proteins. Analysis of the skewed X-chromosome inactivation revealed that extreme skewed X-chromosome inactivation was found in patient #35 (98:2), whereas it was comparatively moderate in patients #347 and #204 (21:79 and 30:70). Our results broaden the variation spectrum of EDA and the phenotype spectrum of XLHED, which could help with clinical diagnosis, treatment, and genetic counseling.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Miao Yu
- Correspondence: (M.Y.); (D.H.); Fax: +86-10-8210-5259 (M.Y.); +86-10-6217-3402 (D.H.)
| | - Dong Han
- Correspondence: (M.Y.); (D.H.); Fax: +86-10-8210-5259 (M.Y.); +86-10-6217-3402 (D.H.)
| |
Collapse
|
21
|
Wagenhäuser L, Rickert V, Sommer C, Wanner C, Nordbeck P, Rost S, Üçeyler N. X-chromosomal inactivation patterns in women with Fabry disease. Mol Genet Genomic Med 2022; 10:e2029. [PMID: 35971858 PMCID: PMC9482401 DOI: 10.1002/mgg3.2029] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 07/06/2022] [Accepted: 07/19/2022] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Although Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA), women may develop severe symptoms. We investigated X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women. PATIENTS AND METHODS We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X-chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity. RESULTS 43/95 (45%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25% distribution) in 6/87 (7%) mouth epithelial cell samples, 31/88 (35%) blood samples, and 9/27 (33%) skin fibroblast samples. Clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels did not show intergroup differences when stratified for X-chromosomal skewing and activity status of the mutated X-chromosome. CONCLUSIONS X-inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns.
Collapse
Affiliation(s)
| | - Vanessa Rickert
- Department of Neurology, University of Würzburg, Würzburg, Germany
| | - Claudia Sommer
- Department of Neurology, University of Würzburg, Würzburg, Germany.,Fabry Centre for Interdisciplinary Therapy Würzburg (FAZIT), University of Würzburg, Würzburg, Germany
| | - Christoph Wanner
- Fabry Centre for Interdisciplinary Therapy Würzburg (FAZIT), University of Würzburg, Würzburg, Germany.,Department of Internal Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany
| | - Peter Nordbeck
- Fabry Centre for Interdisciplinary Therapy Würzburg (FAZIT), University of Würzburg, Würzburg, Germany.,Department of Internal Medicine, Division of Cardiology, University of Würzburg, Würzburg, Germany
| | - Simone Rost
- Institute of Human Genetics, University of Würzburg, Würzburg, Germany
| | - Nurcan Üçeyler
- Department of Neurology, University of Würzburg, Würzburg, Germany.,Fabry Centre for Interdisciplinary Therapy Würzburg (FAZIT), University of Würzburg, Würzburg, Germany
| |
Collapse
|
22
|
A Novel Missense Mutation of Arginine Vasopressin Receptor 2 in a Chinese Family with Congenital Nephrogenic Diabetes Insipidus: X-Chromosome Inactivation in Female CNDI Patients with Heterozygote 814A>G Mutation. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7073158. [PMID: 35865667 PMCID: PMC9296320 DOI: 10.1155/2022/7073158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/10/2022] [Accepted: 06/02/2022] [Indexed: 11/27/2022]
Abstract
Background To identify novel clinical phenotypic signatures of congenital nephrogenic diabetes insipidus (CNDI). Methods A Chinese family with CNDI was recruited for participation in this study. The proband and one of his uncles suffered from polydipsia and polyuria since infancy. The results of clinical testing indicated the diagnosis of CNDI. 10 family members had similar symptoms but did not seek medical advice. Genetic testing of mutations in the coding region of the aquaporin 2 (AQP2) gene and the arginine vasopressin receptor 2 (AVPR2) gene were carried out in 11 family members. Somatic DNA from 5 female family members was used to test for methylation of polymorphic CAG repeats in the human androgen receptor (AR) gene, as an index for X-chromosome inactivation pattern (XCIP). Results AQP2 gene mutations were not found in any family members, but a novel missense mutation (814th base A>G) in exon 2 of the AVPR2 gene was identified in 10 individuals. This mutation leads to a Met 272 Val (GAT-GGT) amino acid substitution. Skewed X-chromosome inactivation patterns of the normal X allele were observed in 4 females with the AVPR2 gene mutation and symptoms of diabetes insipidus, but not in an asymptomatic female with the AVPR2 gene mutation. Conclusions Met 272 Val mutation of the AVPR2 gene was identified as a novel genetic risk factor for CDNI. The clinical NDI phenotype of female carriers with heterozygous AVPR2 mutation may be caused by X-chromosome inactivation induced by dominant methylation of the normal allele of AVPR2 gene.
Collapse
|
23
|
X-Chromosome Inactivation and Related Diseases. Genet Res (Camb) 2022; 2022:1391807. [PMID: 35387179 PMCID: PMC8977309 DOI: 10.1155/2022/1391807] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 02/02/2022] [Accepted: 03/17/2022] [Indexed: 12/12/2022] Open
Abstract
X-chromosome inactivation (XCI) is the form of dosage compensation in mammalian female cells to balance X-linked gene expression levels of the two sexes. Many diseases are related to XCI due to inactivation escape and skewing, and the symptoms and severity of these diseases also largely depend on the status of XCI. They can be divided into 3 types: X-linked diseases, diseases that are affected by XCI escape, and X-chromosome aneuploidy. Here, we review representative diseases in terms of their definition, symptoms, and XCI’s role in the pathogenesis of these diseases.
Collapse
|
24
|
Řeboun M, Sikora J, Magner M, Wiederlechnerová H, Černá A, Poupětová H, Štorkánova G, Mušálková D, Dostálová G, Goláň L, Linhart A, Dvořáková L. Pitfalls of X-chromosome inactivation testing in females with Fabry disease. Am J Med Genet A 2022; 188:1979-1989. [PMID: 35338595 DOI: 10.1002/ajmg.a.62728] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/09/2022] [Accepted: 03/04/2022] [Indexed: 11/07/2022]
Abstract
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding alpha-galactosidase A (AGAL). The impact of X-chromosome inactivation (XCI) on the phenotype of female FD patients remains unclear. In this study we aimed to determine pitfalls of XCI testing in a cohort of 35 female FD patients. XCI was assessed by two methylation-based and two allele-specific expression assays. The results correlated, although some variance among the four assays was observed. GLA transcript analyses identified crossing-over in three patients and detected mRNA instability in three out of four analyzed null alleles. AGAL activity correlated with XCI pattern and was not influenced by the mutation type or by reduced mRNA stability. Therefore, AGAL activity may help to detect crossing-over in patients with unstable GLA alleles. Tissue-specific XCI patterns in six patients, and age-related changes in two patients were observed. To avoid misinterpretation of XCI results in female FD patients we show that (i) a combination of several XCI assays generates more reliable results and minimizes possible biases; (ii) correlating XCI to GLA expression and AGAL activity facilitates identification of cross-over events; (iii) age- and tissue-related XCI specificities of XCI patterning should be considered.
Collapse
Affiliation(s)
- Martin Řeboun
- Diagnostic laboratories of IMD, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Jakub Sikora
- Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.,Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Martin Magner
- Diagnostic laboratories of IMD, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.,Department of Pediatrics, Thomayer University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Helena Wiederlechnerová
- Diagnostic laboratories of IMD, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Alena Černá
- Diagnostic laboratories of IMD, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Helena Poupětová
- Diagnostic laboratories of IMD, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Gabriela Štorkánova
- Diagnostic laboratories of IMD, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Dita Mušálková
- Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Gabriela Dostálová
- Second Department of Internal Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Lubor Goláň
- Second Department of Internal Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Aleš Linhart
- Second Department of Internal Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Lenka Dvořáková
- Diagnostic laboratories of IMD, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| |
Collapse
|
25
|
Catino G, Genovese S, Di Tommaso S, Orlando V, Petti MT, De Bernardi ML, Dallapiccola B, Novelli A, Ulgheri L, Piscopo C, Alesi V. Reciprocal Xp11.4p11.3 microdeletion/microduplication spanning USP9X, DDX3X, and CASK genes in two patients with syndromic intellectual disability. Am J Med Genet A 2022; 188:1836-1847. [PMID: 35238482 DOI: 10.1002/ajmg.a.62694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 02/02/2022] [Accepted: 02/05/2022] [Indexed: 12/13/2022]
Abstract
Only a few patients with deletions or duplications at Xp11.4, bridging USP9X, DDX3X, and CASK genes, have been described so far. Here, we report on a female harboring a de novo Xp11.4p11.3 deletion and a male with an overlapping duplication inherited from an unaffected mother, presenting with syndromic intellectual disability. We discuss the role of USP9X, DDX3X, and CASK genes in human development and describe the effects of Xp11.4 deletion and duplications in female and male patients, respectively.
Collapse
Affiliation(s)
- Giorgia Catino
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Silvia Genovese
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Silvia Di Tommaso
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Valeria Orlando
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Maria Teresa Petti
- Department of Molecular Medicine and Medical Biotechnology, University Federico II, Naples, Italy
| | | | - Bruno Dallapiccola
- Genetics and Rare Disease Research Division, Bambino Gesu Children Hospital, IRCCS, Rome, Italy
| | - Antonio Novelli
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| | - Lucia Ulgheri
- Department of Biomedical Sciences, Clinical Genetics Service, Azienda Ospedaliero-Universitaria, Sassari, Italy
| | - Carmelo Piscopo
- Department of Molecular Medicine and Medical Biotechnology, University Federico II, Naples, Italy
| | - Viola Alesi
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
| |
Collapse
|
26
|
Rodrigues B, Gonçalves A, Sousa V, Maia N, Marques I, Vale-Fernandes E, Santos R, Nogueira AJA, Jorge P. Use of the FMR1 Gene Methylation Status to Assess the X-Chromosome Inactivation Pattern: A Stepwise Analysis. Genes (Basel) 2022; 13:419. [PMID: 35327973 PMCID: PMC8951761 DOI: 10.3390/genes13030419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 11/23/2022] Open
Abstract
X-chromosome inactivation (XCI) is a developmental process to compensate the imbalance in the dosage of X-chromosomal genes in females. A skewing of the XCI pattern may suggest a carrier status for an X-linked disease or explain the presence of a severe phenotype. In these cases, it is important to determine the XCI pattern, conventionally using the gold standard Human Androgen-Receptor Assay (HUMARA), based on the analysis of the methylation status at a polymorphic CAG region in the first exon of the human androgen receptor gene (AR). The aim of this study was to evaluate whether the methylation status of the fragile mental retardation protein translational regulator gene (FMR1) can provide an XCI pattern similar to that obtained by HUMARA. A set of 48 female carriers of FMR1 gene normal-sized alleles was examined using two assays: HUMARA and a FMR1 methylation PCR (mPCR). Ranges were defined to establish the XCI pattern using the methylation pattern of the FMR1 gene by mPCR. Overall, a 77% concordance of the XCI patterns was obtained between the two assays, which led us to propose a set of key points and a stepwise analysis towards obtaining an accurate result for the XCI pattern and to minimize the underlying pitfalls.
Collapse
Affiliation(s)
- Bárbara Rodrigues
- Molecular Genetics Unit, Centro de Genética Médica Dr. Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), 4099-028 Porto, Portugal; (B.R.); (A.G.); (V.S.); (N.M.); (I.M.); (R.S.)
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal;
- ITR—Laboratory for Integrative and Translational Research in Population Health, 4050-313 Porto, Portugal
| | - Ana Gonçalves
- Molecular Genetics Unit, Centro de Genética Médica Dr. Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), 4099-028 Porto, Portugal; (B.R.); (A.G.); (V.S.); (N.M.); (I.M.); (R.S.)
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal;
- ITR—Laboratory for Integrative and Translational Research in Population Health, 4050-313 Porto, Portugal
| | - Vanessa Sousa
- Molecular Genetics Unit, Centro de Genética Médica Dr. Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), 4099-028 Porto, Portugal; (B.R.); (A.G.); (V.S.); (N.M.); (I.M.); (R.S.)
| | - Nuno Maia
- Molecular Genetics Unit, Centro de Genética Médica Dr. Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), 4099-028 Porto, Portugal; (B.R.); (A.G.); (V.S.); (N.M.); (I.M.); (R.S.)
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal;
- ITR—Laboratory for Integrative and Translational Research in Population Health, 4050-313 Porto, Portugal
| | - Isabel Marques
- Molecular Genetics Unit, Centro de Genética Médica Dr. Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), 4099-028 Porto, Portugal; (B.R.); (A.G.); (V.S.); (N.M.); (I.M.); (R.S.)
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal;
- ITR—Laboratory for Integrative and Translational Research in Population Health, 4050-313 Porto, Portugal
| | - Emídio Vale-Fernandes
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal;
- ITR—Laboratory for Integrative and Translational Research in Population Health, 4050-313 Porto, Portugal
- Centre for Medically Assisted Procreation/Public Gamete Bank, Centro Materno-Infantil do Norte Dr. Albino Aroso (CMIN), Centro Hospitalar Universitário do Porto (CHUPorto), 4050-651 Porto, Portugal
| | - Rosário Santos
- Molecular Genetics Unit, Centro de Genética Médica Dr. Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), 4099-028 Porto, Portugal; (B.R.); (A.G.); (V.S.); (N.M.); (I.M.); (R.S.)
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal;
- ITR—Laboratory for Integrative and Translational Research in Population Health, 4050-313 Porto, Portugal
| | - António J. A. Nogueira
- CESAM—Center for Environmental and Marine Studies, Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - Paula Jorge
- Molecular Genetics Unit, Centro de Genética Médica Dr. Jacinto Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), 4099-028 Porto, Portugal; (B.R.); (A.G.); (V.S.); (N.M.); (I.M.); (R.S.)
- UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS—School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal;
- ITR—Laboratory for Integrative and Translational Research in Population Health, 4050-313 Porto, Portugal
| |
Collapse
|
27
|
Qin S, Wang X, Wang J. Identification of an SRY-negative 46,XX infertility male with a heterozygous deletion downstream of SOX3 gene. Mol Cytogenet 2022; 15:2. [PMID: 35164824 PMCID: PMC8842887 DOI: 10.1186/s13039-022-00580-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/28/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
A male individual with a karyotype of 46,XX is very rare. We explored the genetic aetiology of an infertility male with a kayrotype of 46,XX and SRY negative.
Methods
The peripheral blood sample was collected from the patient and subjected to a few genetic testing, including chromosomal karyotyping, azoospermia factor (AZF) deletion, short tandem repeat (STR) analysis for AMELX, AMELY and SRY, fluorescence in situ hybridization (FISH) with specific probes for CSP 18/CSP X/CSP Y/SRY, chromosomal microarray analysis (CMA) for genomic copy number variations(CNVs), whole-genome analysis(WGA) for genomic SNV&InDel mutation, and X chromosome inactivation (XCI) analysis.
Results
The patient had a karyotype of 46,XX. AZF analysis showed that he missed the AZF region (including a, b and c) and SRY gene. STR assay revealed he possessed the AMELX in the X chromosome, but he had no the AMELY and SRY in the Y chromosome. FISH analysis with CSP X/CSP Y/SRY showed only two X centromeric signals, but none Y chromosome and SRY. The above results of the karyotype, FISH and STR analysis did not suggest a Y chromosome chimerism existed in the patient's peripheral blood. The result of the CMA indicated a heterozygous deletion with an approximate size of 867 kb in Xq27.1 (hg19: chrX: 138,612,879–139,480,163 bp), located at 104 kb downstream of SOX3 gene, including F9, CXorf66, MCF2 and ATP11C. WGA also displayed the above deletion fragment but did not present known pathogenic or likely pathogenic SNV&InDel mutation responsible for sex determination and development. XCI assay showed that he had about 75% of the X chromosome inactivated.
Conclusions
Although the pathogenicity of 46,XX male patients with SRY negative remains unclear, SOX3 expression of the acquired function may be associated with partial testis differentiation of these patients. Therefore, the CNVs analysis of the SOX3 gene and its regulatory region should be performed routinely for these patients.
Collapse
|
28
|
Liu L, Chen H, Sun C, Zhang J, Wang J, Du M, Li J, Di L, Shen J, Geng S, Pang Y, Luo Y, Wu C, Fu Y, Zheng Z, Wang J, Huang Y. Low-frequency somatic copy number alterations in normal human lymphocytes revealed by large-scale single-cell whole-genome profiling. Genome Res 2021; 32:44-54. [PMID: 34963662 PMCID: PMC8744674 DOI: 10.1101/gr.275453.121] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 11/15/2021] [Indexed: 11/29/2022]
Abstract
Genomic-scale somatic copy number alterations in healthy humans are difficult to investigate because of low occurrence rates and the structural variations’ stochastic natures. Using a Tn5-transposase-assisted single-cell whole-genome sequencing method, we sequenced over 20,000 single lymphocytes from 16 individuals. Then, with the scale increased to a few thousand single cells per individual, we found that about 7.5% of the cells had large-size copy number alterations. Trisomy 21 was the most prevalent aneuploid event among all autosomal copy number alterations, whereas monosomy X occurred most frequently in over-30-yr-old females. In the monosomy X single cells from individuals with phased genomes and identified X-inactivation ratios in bulk, the inactive X Chromosomes were lost more often than the active ones.
Collapse
|
29
|
Apkon S, Kinnett K, Cripe L, Duan D, Jackson JL, Kornegay JN, Mah ML, Nelson SF, Rao V, Scavina M, Wong BL, Flanigan KM. Parent Project Muscular Dystrophy Females with Dystrophinopathy Conference, Orlando, Florida June 26 - June 27, 2019. J Neuromuscul Dis 2021; 8:315-322. [PMID: 33361607 PMCID: PMC10497321 DOI: 10.3233/jnd-200555] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Susan Apkon
- Department of Physical Medicine and Rehabilitation, University of Colorado Denver and Children’s Hospital Colorado, Aurora, CO, USA
| | - Kathi Kinnett
- Parent Project Muscular Dystrophy, Hackensack, NJ, USA
| | - Linda Cripe
- The Heart Center, Nationwide Children’s Hospital and the Ohio State University, Columbus, OH, USA
| | - Dongsheng Duan
- Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
| | - Jamie L. Jackson
- Center for Biobehavioral Health, Abigail Wexner Research Institute at Nationwide Children’s Hospital; Assistant Professor of Pediatrics and Psychology, The Ohio State University, Columbus, OH, USA
| | - Joe N. Kornegay
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, 4458 TAMU, College Station, TX, USA
| | - May Ling Mah
- The Heart Center, Nationwide Children’s Hospital and the Ohio State University, Columbus, OH, USA
| | - Stanley F. Nelson
- Department of Human Genetics, Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Vamshi Rao
- Department of Pediatrics, Division of Neurology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL USA
| | - Mena Scavina
- Department of Neurology, Nemours/duPont Hospital for Children, Wilmington, DE, USA
| | - Brenda L. Wong
- Department of Pediatrics and Neurology, University of Massachusetts Medical School, Worcester, MA USA
| | - Kevin M. Flanigan
- Center for Gene Therapy, Nationwide Children’s Hospital and Departments of Pediatrics and Neurology, Ohio State University, Columbus, Ohio, USA
| |
Collapse
|
30
|
Barreto VM, Kubasova N, Alves-Pereira CF, Gendrel AV. X-Chromosome Inactivation and Autosomal Random Monoallelic Expression as "Faux Amis". Front Cell Dev Biol 2021; 9:740937. [PMID: 34631717 PMCID: PMC8495168 DOI: 10.3389/fcell.2021.740937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/30/2021] [Indexed: 12/23/2022] Open
Abstract
X-chromosome inactivation (XCI) and random monoallelic expression of autosomal genes (RMAE) are two paradigms of gene expression regulation where, at the single cell level, genes can be expressed from either the maternal or paternal alleles. X-chromosome inactivation takes place in female marsupial and placental mammals, while RMAE has been described in mammals and also other species. Although the outcome of both processes results in random monoallelic expression and mosaicism at the cellular level, there are many important differences. We provide here a brief sketch of the history behind the discovery of XCI and RMAE. Moreover, we review some of the distinctive features of these two phenomena, with respect to when in development they are established, their roles in dosage compensation and cellular phenotypic diversity, and the molecular mechanisms underlying their initiation and stability.
Collapse
Affiliation(s)
- Vasco M Barreto
- Chronic Diseases Research Centre, CEDOC, Nova Medical School, Lisbon, Portugal
| | - Nadiya Kubasova
- Chronic Diseases Research Centre, CEDOC, Nova Medical School, Lisbon, Portugal
| | - Clara F Alves-Pereira
- Department of Genetics, Smurfit Institute of Genetics, Trinity College Dublin, University of Dublin, Dublin, Ireland
| | - Anne-Valerie Gendrel
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| |
Collapse
|
31
|
Simonetti L, Ferreira LGA, Vidi AC, de Souza JS, Kunii IS, Melaragno MI, de Mello CB, Carvalheira G, Dias da Silva MR. Intelligence Quotient Variability in Klinefelter Syndrome Is Associated With GTPBP6 Expression Under Regulation of X-Chromosome Inactivation Pattern. Front Genet 2021; 12:724625. [PMID: 34616429 PMCID: PMC8488338 DOI: 10.3389/fgene.2021.724625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/24/2021] [Indexed: 11/25/2022] Open
Abstract
Klinefelter syndrome (KS) displays a broad dysmorphological, endocrinological, and neuropsychological clinical spectrum. We hypothesized that the neurocognitive dysfunction present in KS relies on an imbalance in X-chromosome gene expression. Thus, the X-chromosome inactivation (XCI) pattern and neurocognitive X-linked gene expression were tested and correlated with intelligence quotient (IQ) scores. We evaluated 11 KS patients by (a) IQ assessment, (b) analyzing the XCI patterns using both HUMARA and ZDHHC15 gene assays, and (c) blood RT-qPCR to investigate seven X-linked genes related to neurocognitive development (GTPBP6, EIF2S3, ITM2A, HUWE1, KDM5C, GDI1, and VAMP7) and XIST in comparison with 14 (male and female) controls. Considering IQ 80 as the standard minimum reference, we verified that the variability in IQ scores in KS patients seemed to be associated with the XCI pattern. Seven individuals in the KS group presented a random X-inactivation (RXI) and lower average IQ than the four individuals who presented a skewed X-inactivation (SXI) pattern. The evaluation of gene expression showed higher GTPBP6 expression in KS patients with RXI than in controls (p = 0.0059). Interestingly, the expression of GTPBP6 in KS patients with SXI did not differ from that observed in controls. Therefore, our data suggest for the first time that GTPBP6 expression is negatively associated with full-scale IQ under the regulation of the type of XCI pattern. The SXI pattern may regulate GTPBP6 expression, thereby dampening the impairment in cognitive performance and playing a role in intelligence variability in individuals with KS, which warrants further mechanistic investigations.
Collapse
Affiliation(s)
- Luciane Simonetti
- Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Lucas G A Ferreira
- Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.,Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Angela Cristina Vidi
- Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.,Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Janaina Sena de Souza
- Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Ilda S Kunii
- Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Maria Isabel Melaragno
- Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Claudia Berlim de Mello
- Department of Psychobiology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Gianna Carvalheira
- Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Magnus R Dias da Silva
- Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.,Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| |
Collapse
|
32
|
Viggiano E, Politano L. X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis. Int J Mol Sci 2021; 22:ijms22147663. [PMID: 34299283 PMCID: PMC8304911 DOI: 10.3390/ijms22147663] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 12/27/2022] Open
Abstract
Anderson-Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by a deficiency of α-galactosidase A. The incidence ranges between 1: 40,000 and 1:117,000 of live male births. In Italy, an estimate of incidence is available only for the north-western Italy, where it is of approximately 1:4000. Clinical symptoms include angiokeratomas, corneal dystrophy, and neurological, cardiac and kidney involvement. The prevalence of symptomatic female carriers is about 70%, and in some cases, they can exhibit a severe phenotype. Previous studies suggest a correlation between skewed X chromosome inactivation and symptoms in carriers of X-linked disease, including Fabry disease. In this review, we briefly summarize the disease, focusing on the clinical symptoms of carriers and analysis of the studies so far published in regards to X chromosome inactivation pattern, and manifesting Fabry carriers. Out of 151 records identified, only five reported the correlation between the analysis of XCI in leukocytes and the related phenotype in Fabry carriers, in particular evaluating the Mainz Severity Score Index or cardiac involvement. The meta-analysis did not show any correlation between MSSI or cardiac involvement and skewed XCI, likely because the analysis of XCI in leukocytes is not useful for predicting the phenotype in Fabry carriers.
Collapse
Affiliation(s)
- Emanuela Viggiano
- Department of Prevention, UOC Hygiene Service and Public Health, ASL Roma 2, 00142 Rome, Italy
- Correspondence: (E.V.); (L.P.)
| | - Luisa Politano
- Cardiomyology and Medical Genetics, Department of Experimental Medicine, Luigi Vanvitelli University, 80138 Naples, Italy
- Correspondence: (E.V.); (L.P.)
| |
Collapse
|
33
|
A statistical measure for the skewness of X chromosome inactivation for quantitative traits and its application to the MCTFR data. BMC Genom Data 2021; 22:24. [PMID: 34215184 PMCID: PMC8254321 DOI: 10.1186/s12863-021-00978-z] [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: 08/18/2020] [Accepted: 06/17/2021] [Indexed: 11/24/2022] Open
Abstract
Background X chromosome inactivation (XCI) is that one of two chromosomes in mammalian females is silenced during early development of embryos. There has been a statistical measure for the degree of the skewness of XCI for qualitative traits. However, no method is available for such task at quantitative trait loci. Results In this article, we extend the existing statistical measure for the skewness of XCI for qualitative traits, and the likelihood ratio, Fieller’s and delta methods for constructing the corresponding confidence intervals, and make them accommodate quantitative traits. The proposed measure is a ratio of two linear regression coefficients when association exists. Noting that XCI may cause variance heterogeneity of the traits across different genotypes in females, we obtain the point estimate and confidence intervals of the measure by incorporating such information. The hypothesis testing of the proposed methods is also investigated. We conduct extensive simulation studies to assess the performance of the proposed methods. Simulation results demonstrate that the median of the point estimates of the measure is very close to the pre-specified true value. The likelihood ratio and Fieller’s methods control the size well, and have the similar test power and accurate coverage probability, which perform better than the delta method. So far, we are not aware of any association study for the X-chromosomal loci in the Minnesota Center for Twin and Family Research data. So, we apply our proposed methods to these data for their practical use and find that only the rs792959 locus, which is simultaneously associated with the illicit drug composite score and behavioral disinhibition composite score, may undergo XCI skewing. However, this needs to be confirmed by molecular genetics. Conclusions We recommend the Fieller’s method in practical use because it is a non-iterative procedure and has the similar performance to the likelihood ratio method. Supplementary Information The online version contains supplementary material available at 10.1186/s12863-021-00978-z.
Collapse
|
34
|
X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay. Clin Exp Nephrol 2021; 25:1224-1230. [PMID: 34128148 DOI: 10.1007/s10157-021-02099-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 06/09/2021] [Indexed: 01/04/2023]
Abstract
BACKGROUND Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A. Males are usually severely affected, while females have a wide range of disease severity. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to ascertain the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes. METHODS We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing. Fabry Stabilization Index was used to determine the clinical severity. RESULTS Skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with low ⍺-galactosidase A activity. In the remaining cases, no skewing was observed, even in the case with the highest total severity score (99.2%). CONCLUSION We conclude that skewed XCI could not explain the severity of female Fabry disease and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.
Collapse
|
35
|
trans-Acting Factors and cis Elements Involved in the Human Inactive X Chromosome Organization and Compaction. Genet Res (Camb) 2021; 2021:6683460. [PMID: 34035662 PMCID: PMC8121581 DOI: 10.1155/2021/6683460] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 04/06/2021] [Accepted: 04/30/2021] [Indexed: 11/23/2022] Open
Abstract
During X chromosome inactivation, many chromatin changes occur on the future inactive X chromosome, including acquisition of a variety of repressive covalent histone modifications, heterochromatin protein associations, and DNA methylation of promoters. Here, we summarize trans-acting factors and cis elements that have been shown to be involved in the human inactive X chromosome organization and compaction.
Collapse
|
36
|
Juchniewicz P, Piotrowska E, Kloska A, Podlacha M, Mantej J, Węgrzyn G, Tukaj S, Jakóbkiewicz-Banecka J. Dosage Compensation in Females with X-Linked Metabolic Disorders. Int J Mol Sci 2021; 22:ijms22094514. [PMID: 33925963 PMCID: PMC8123450 DOI: 10.3390/ijms22094514] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 01/19/2023] Open
Abstract
Through the use of new genomic and metabolomic technologies, our comprehension of the molecular and biochemical etiologies of genetic disorders is rapidly expanding, and so are insights into their varying phenotypes. Dosage compensation (lyonization) is an epigenetic mechanism that balances the expression of genes on heteromorphic sex chromosomes. Many studies in the literature have suggested a profound influence of this phenomenon on the manifestation of X-linked disorders in females. In this review, we summarize the clinical and genetic findings in female heterozygotic carriers of a pathogenic variant in one of ten selected X-linked genes whose defects result in metabolic disorders.
Collapse
Affiliation(s)
- Patrycja Juchniewicz
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (P.J.); (A.K.); (J.J.-B.)
| | - Ewa Piotrowska
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (M.P.); (J.M.); (G.W.); (S.T.)
- Correspondence: ; Tel.: +48-58-523-6040
| | - Anna Kloska
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (P.J.); (A.K.); (J.J.-B.)
| | - Magdalena Podlacha
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (M.P.); (J.M.); (G.W.); (S.T.)
| | - Jagoda Mantej
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (M.P.); (J.M.); (G.W.); (S.T.)
| | - Grzegorz Węgrzyn
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (M.P.); (J.M.); (G.W.); (S.T.)
| | - Stefan Tukaj
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (M.P.); (J.M.); (G.W.); (S.T.)
| | - Joanna Jakóbkiewicz-Banecka
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland; (P.J.); (A.K.); (J.J.-B.)
| |
Collapse
|
37
|
Körber L, Schneider H, Fleischer N, Maier-Wohlfart S. No evidence for preferential X-chromosome inactivation as the main cause of divergent phenotypes in sisters with X-linked hypohidrotic ectodermal dysplasia. Orphanet J Rare Dis 2021; 16:98. [PMID: 33622384 PMCID: PMC7901220 DOI: 10.1186/s13023-021-01735-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 02/09/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic disorder, affects the normal development of ectodermal derivatives, such as hair, skin, teeth, and sweat glands. It is caused by pathogenic variants of the gene EDA and defined by a triad of hypotrichosis, hypo- or anodontia, and hypo- or anhidrosis which may lead to life-threatening hyperthermia. Although female carriers are less severely affected than male patients, they display symptoms, too, with high phenotypic variability. This study aimed to elucidate whether phenotypic differences in female XLHED patients with identical EDA genotypes might be explained by deviating X-chromosome inactivation (XI) patterns. METHODS Six families, each consisting of two sisters with the same EDA variant and their parents (with either mother or father being carrier of the variant), participated in this study. XLHED-related data like sweating ability, dental status, facial dysmorphism, and skin issues were assessed. We determined the women`s individual XI patterns in peripheral blood leukocytes by the human androgen receptor assay and collated the results with phenotypic features. RESULTS The surprisingly large inter- and intrafamilial variability of symptoms in affected females was not explicable by the pathogenic variants. Our cohort showed no higher rate of nonrandom XI in peripheral blood leukocytes than the general female population. Furthermore, skewed XI patterns in favour of the mutated alleles were not associated with more severe phenotypes. CONCLUSIONS We found no evidence for preferential XI in female XLHED patients and no distinct correlation between XLHED-related phenotypic features and XI patterns. Phenotypic variability seems to be evoked by other genetic or epigenetic factors.
Collapse
Affiliation(s)
- Laura Körber
- Center for Ectodermal Dysplasias and Department of Pediatrics, University Hospital Erlangen, Loschgestr. 15, 91054, Erlangen, Germany
| | - Holm Schneider
- Center for Ectodermal Dysplasias and Department of Pediatrics, University Hospital Erlangen, Loschgestr. 15, 91054, Erlangen, Germany
| | | | - Sigrun Maier-Wohlfart
- Center for Ectodermal Dysplasias and Department of Pediatrics, University Hospital Erlangen, Loschgestr. 15, 91054, Erlangen, Germany.
| |
Collapse
|
38
|
Mastrangelo A, Giani M, Groppali E, Castorina P, Soldà G, Robusto M, Fallerini C, Bruttini M, Renieri A, Montini G. X-Linked Alport Syndrome in Women: Genotype and Clinical Course in 24 Cases. Front Med (Lausanne) 2020; 7:580376. [PMID: 33330536 PMCID: PMC7719790 DOI: 10.3389/fmed.2020.580376] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 10/19/2020] [Indexed: 11/30/2022] Open
Abstract
Objectives: X-linked Alport syndrome (XLAS) females are at risk of developing proteinuria and chronic kidney damage (CKD). The aim of this study is to evaluate the genotype-phenotype correlation in this rare population. Materials and Methods: This is a prospective, observational study of XLAS females, confirmed by a pathogenic mutation in COL4A5 and renal ultrastructural evaluation. Proteinuria, renal function and extrarenal involvement were monitored during follow-up. Patients were divided in 2 groups, according to mutations in COL4A5: missense (Group 1) and non-missense variants (Group 2). Results: Twenty-four XLAS females, aged 10.6 ± 10.4 years at clinical onset (mean follow-up: 13.1 ± 12.6 years) were recruited between 2000 and 2017 at a single center. In group 1 there were 10 patients and in group 2, 14 (mean age at the end of follow-up: 24.9 ± 13.6 and 23.2 ± 13.8 years, respectively). One patient in Group 1 and 9 in Group 2 (p = 0.013) developed proteinuria during follow-up. Mean eGFR at last follow-up was lower in Group 2 (p = 0.027), where two patients developed CKD. No differences in hearing loss were documented among the two groups. Two patients in Group 2 carried one mutation in both COL4A5 and COL4A3 (digenic inheritance) and were proteinuric. In one family, the mother presented only hematuria while the daughter was proteinuric and presented a greater inactivation of the X chromosome carrying the wild-type allele. Conclusions: The appearance of proteinuria and CKD is more frequent in patients with severe variants. Carrying digenic inheritance and skewed XCI seem to be additional risk factors for proteinuria in XLAS females.
Collapse
Affiliation(s)
- Antonio Mastrangelo
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marisa Giani
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Elena Groppali
- Department of Pediatrics, V. Buzzi Children's Hospital, Milan, Italy
| | | | - Giulia Soldà
- Dipartimento di Scienze Biomediche, Humanitas University, Milan, Italy.,Humanitas Clinical and Research Center, Milan, Italy
| | - Michela Robusto
- Experimental Therapeutics Program, Istituto FIRC di Oncologia Molecolare-Fondazione Italiana per la Ricerca sul Cancro Institute of Molecular Oncology Foundation, Milan, Italy
| | | | - Mirella Bruttini
- Azienda Ospedaliera Universitaria Senese, Medical Genetics, University of Siena, Siena, Italy
| | - Alessandra Renieri
- Azienda Ospedaliera Universitaria Senese, Medical Genetics, University of Siena, Siena, Italy
| | - Giovanni Montini
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,Giuliana and Bernardo Caprotti Chair of Pediatrics, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| |
Collapse
|
39
|
Sandow R, Scott FP, Schluter PJ, Rolnik DL, Menezes M, Nisbet D, McLennan AC. Increasing maternal age is not a significant cause of false‐positive results for monosomy X in non‐invasive prenatal testing. Prenat Diagn 2020; 40:1466-1473. [DOI: 10.1002/pd.5790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 03/23/2020] [Accepted: 07/12/2020] [Indexed: 01/15/2023]
Affiliation(s)
- Rhiannon Sandow
- Sydney Ultrasound for Women, Monash IVF Group Sydney New South Wales Australia
- Department of Cancer Genetics Royal Prince Alfred Hospital Camperdown New South Wales Australia
| | - Fergus P. Scott
- Sydney Ultrasound for Women, Monash IVF Group Sydney New South Wales Australia
- Faculty of Medicine University of New South Wales Randwick New South Wales Australia
| | - Philip J. Schluter
- School of Health Sciences University of Canterbury – Te Whare Wānanga o Waitaha Christchurch New Zealand
- School of Clinical Medicine, Primary Care Clinical Unit The University of Queensland Brisbane Queensland Australia
| | - Daniel L. Rolnik
- Department of Obstetrics and Gynaecology Monash University Melbourne Victoria Australia
| | - Melody Menezes
- Monash Ultrasound for Women Monash IVF Group Melbourne Victoria Australia
- Department of Paediatrics The University of Melbourne Melbourne Victoria Australia
| | - Deborah Nisbet
- Department of Ultrasound Services The Royal Women's Hospital Parkville Victoria Australia
- Women's Ultrasound Melbourne East Melbourne Victoria Australia
| | - Andrew C. McLennan
- Sydney Ultrasound for Women, Monash IVF Group Sydney New South Wales Australia
- Discipline of Obstetrics, Gynaecology and Neonatology The University of Sydney Sydney New South Wales Australia
| |
Collapse
|
40
|
Polat S, Karaburgu S, Unluhizarci K, Dündar M, Özkul Y, Arslan YK, Karaca Z, Kelestimur F. The role of androgen receptor CAG repeat polymorphism in androgen excess disorder and idiopathic hirsutism. J Endocrinol Invest 2020; 43:1271-1281. [PMID: 32166698 DOI: 10.1007/s40618-020-01215-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Accepted: 03/04/2020] [Indexed: 12/19/2022]
Abstract
PURPOSE The study aimed to investigate whether repeat number in the androgen receptor (AR) gene has any contribution to phenotypes of the disease of androgen excess (polycystic ovary syndrome (PCOS), idiopathic hyperandrogenemia (IHA) and idiopathic hirsutism (IH) in a cohort of Turkish women. METHODS Three hundred and fifty-four voluntary premenopausal women (172 healthy controls and 182 patients with androgen excess disorders and idiopathic hirsutism) 18-45 years of age seen at an outpatient endocrine clinic at Erciyes University Hospital between January 2013 and December 2014 were included. All volunteers have undergone physical examination and biochemical evaluation. The polymorphic (CAG)n repeat of the human AR was determined by fragment analyses. RESULTS Detailed clinical analyses of the patients ended up with 137 PCOS, 24 IHA, and 21 IH. Pairwise comparisons revealed the CAG repeat number differences between the PCOS and controls (p = 0.005) and IH and controls (p = 0.020). Women with CAG repeat length ≤ 17 had a significantly increased twofold risk for PCOS than those women with > 17 CAG repeats OR: 2.0 (95% CI 1.2-3.3, p = 0.005). Women with CAG repeat length ≤ 17 had a significantly increased threefold risk for IH than those women with > 17 CAG repeats OR: 2.9 (95% CI 1.2-7.3, p = 0.020). When correlation analysis was performed, a weak negative correlation was detected between the short allele and FGS score (r = - 0.131, p = 0.013) and a positive relationship between total testosterone and longer allele in the IHA group (r = 0.425, p = 0.039). Median repeat length of the shorter allele between oligomenorrhea and woman with normal menstrual cycle was found to be statistically significant (p = 0.017). CONCLUSION This study indicated that the risk of PCOS and IH is associated with the inheritance of ARs with shorter CAG repeats.
Collapse
Affiliation(s)
- S Polat
- Department of Medical Genetics, Medical Faculty, Erzincan University, Basbaglar Mah, 24100, Erzincan, Merkez, Turkey.
| | - S Karaburgu
- Department of Endocrinology, Medical Faculty, Erciyes University, Kayseri, Turkey
| | - K Unluhizarci
- Department of Endocrinology, Medical Faculty, Erciyes University, Kayseri, Turkey
| | - M Dündar
- Department of Medical Genetics, Medical Faculty, Erciyes University, Kayseri, Turkey
| | - Y Özkul
- Department of Medical Genetics, Medical Faculty, Erciyes University, Kayseri, Turkey
| | - Y K Arslan
- Department of Biostatistics, Medical Faculty, Erzincan University, Erzincan, Turkey
| | - Z Karaca
- Department of Endocrinology, Medical Faculty, Erciyes University, Kayseri, Turkey
| | - F Kelestimur
- Department of Endocrinology, Medical Faculty, Erciyes University, Kayseri, Turkey
- Department of Endocrinology, Medical Faculty, Yeditepe University, İstanbul, Turkey
| |
Collapse
|
41
|
Zhang X, Li Y, Ma L, Zhang G, Liu M, Wang C, Zheng Y, Li R. A new sex-specific underlying mechanism for female schizophrenia: accelerated skewed X chromosome inactivation. Biol Sex Differ 2020; 11:39. [PMID: 32680558 PMCID: PMC7368719 DOI: 10.1186/s13293-020-00315-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 07/02/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND X chromosome inactivation (XCI) is the mechanism by which the X-linked gene dosage is adjusted between the sexes. Evidence shows that many sex-specific diseases have their basis in X chromosome biology. While female schizophrenia patients often have a delayed age of disease onset and clinical phenotypes that are different from those of males, it is unknown whether the sex differences in schizophrenia are associated with X-linked gene dosage and the choice of X chromosome silencing in female cells. Previous studies demonstrated that sex chromosome aneuploidies may be related to the pathogeneses of some psychiatric diseases. Here, we examined the changes in skewed XCI in patients with schizophrenia. METHODS A total of 109 female schizophrenia (SCZ) patients and 80 age- and sex-matched healthy controls (CNTLs) were included in this study. We evaluated clinical features including disease onset age, disease duration, clinical symptoms by the Positive and Negative Syndrome Scale (PANSS) and antipsychotic treatment dosages. The XCI skewing patterns were analyzed by the methylation profile of the HUMARA gene found in DNA isolated from SCZ patient and CNTL leukocytes in the three age groups. RESULTS First, we found that the frequency of skewed XCI in SCZ patients was 4 times more than that in the age- and sex-matched CNTLs (p < 0.01). Second, we found an earlier onset of severe XCI skewing in the SCZ patients than in CNTLs. Third, we demonstrated a close relationship between the severity of skewed XCI and schizophrenic symptoms (PANSS score ≥ 90) as well as the age of disease onset. Fourth, we demonstrated that the skewed XCI in SCZ patients was not transmitted from the patients' mothers. LIMITATIONS The XCI skewing pattern might differ depending on tissues or organs. Although this is the first study to explore skewed XCI in SCZ, in the future, samples from different tissues or cells in SCZ patients might be important for understanding the impact of skewed XCI in this disease. CONCLUSION Our study, for the first time, investigated skewed XCI in female SCZ patients and presented a potential mechanism for the sex differences in SCZ. Our data also suggested that XCI might be a potential target for the development of female-specific interventions for SCZ.
Collapse
Affiliation(s)
- Xinzhu Zhang
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
| | - Yuhong Li
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
| | - Lei Ma
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Guofu Zhang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Min Liu
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Chuanyue Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Yi Zheng
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
| | - Rena Li
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China. .,The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China.
| |
Collapse
|
42
|
Fontana L, Bedeschi MF, Cagnoli GA, Costanza J, Persico N, Gangi S, Porro M, Ajmone PF, Colapietro P, Santaniello C, Crippa M, Sirchia SM, Miozzo M, Tabano S. (Epi)genetic profiling of extraembryonic and postnatal tissues from female monozygotic twins discordant for Beckwith-Wiedemann syndrome. Mol Genet Genomic Med 2020; 8:e1386. [PMID: 32627967 PMCID: PMC7507324 DOI: 10.1002/mgg3.1386] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 05/26/2020] [Accepted: 06/01/2020] [Indexed: 12/19/2022] Open
Abstract
Background Beckwith–Wiedemann syndrome (BWS) is an overgrowth disorder caused by defects at the 11p15.5 imprinted region. Many cases of female monozygotic (MZ) twins discordant for BWS have been reported, but no definitive conclusions have been drawn regarding the link between epigenetic defects, twinning process, and gender. Here, we report a comprehensive characterization and follow‐up of female MZ twins discordant for BWS. Methods Methylation pattern at 11p15.5 and multilocus methylation disturbance (MLID) profiling were performed by pyrosequencing and MassARRAY in placental/umbilical cord samples and postnatal tissues. Whole‐exome sequencing was carried out to identify MLID causative mutations. X‐chromosome inactivation (XCI) was determined by HUMARA test. Results Both twins share KCNQ1OT1:TSS‐DMR loss of methylation (LOM) and MLID in blood and the epigenetic defect remained stable in the healthy twin over time. KCNQ1OT1:TSS‐DMRLOM was nonhomogeneously distributed in placental samples and the twins showed the same severely skewed XCI pattern. No MLID‐causative mutations were identified. Conclusion This is the first report on BWS‐discordant twins with methylation analyses extended to extraembryonic tissues. The results suggest that caution is required when attempting prenatal diagnosis in similar cases. Although the causative mechanism underlying LOM remains undiscovered, the XCI pattern and mosaic LOM suggest that both twinning and LOM/MLID occurred after XCI commitment.
Collapse
Affiliation(s)
- Laura Fontana
- Medical Genetics, Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milano, Italy.,Research Laboratories Coordination Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Maria F Bedeschi
- Medical Genetics Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Giulia A Cagnoli
- Medical Genetics Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Jole Costanza
- Research Laboratories Coordination Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Nicola Persico
- Obstetrics and Gynecology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.,Department of ClinicalSciences and Community Health, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Silvana Gangi
- NICU, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Matteo Porro
- Pediatric Physical Medicine & Rehabilitation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Paola F Ajmone
- Child and AdolescentNeuropsychiatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Patrizia Colapietro
- Medical Genetics, Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milano, Italy.,Research Laboratories Coordination Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Carlo Santaniello
- Research Laboratories Coordination Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Milena Crippa
- Medical Cytogenetics& Human Molecular Genetics, Istituto Auxologico Italiano-IRCCS, Milano, Italy
| | - Silvia M Sirchia
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milano, Italy
| | - Monica Miozzo
- Medical Genetics, Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milano, Italy.,Research Laboratories Coordination Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Silvia Tabano
- Medical Genetics, Department of Pathophysiology & Transplantation, Università degli Studi di Milano, Milano, Italy.,Laboratory of Medical Genetics, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan, Italy
| |
Collapse
|
43
|
Understanding the Landscape of X-linked Variants Causing Intellectual Disability in Females Through Extreme X Chromosome Inactivation Skewing. Mol Neurobiol 2020; 57:3671-3684. [DOI: 10.1007/s12035-020-01981-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 06/08/2020] [Indexed: 12/14/2022]
|
44
|
Salvetti AP, Nanda A, MacLaren RE. RPGR-Related X-Linked Retinitis Pigmentosa Carriers with a Severe "Male Pattern". Ophthalmologica 2020; 244:60-67. [PMID: 32434206 DOI: 10.1159/000503687] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Accepted: 09/25/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND X-linked retinitis pigmentosa (XLRP) due to mutations in the RPGR gene is a very severe form of RP, resulting in rapid disease progression and retinal dysfunction. Female carriers do not usually report symptoms. However, it has reported that carriers of XLRP can have a significant visual and retinal impairment. OBJECTIVES To report a detailed description of 3 cases of severely affected females who presented with a "male" phenotype and have posed challenges at diagnosis, due to the apparent autosomal dominant family history. METHOD Autofluorescence imaging (AF), colour imaging and optical coherence tomography (OCT) were performed. Confirmation of the genetic mutation was obtained by Sanger genetic sequencing. In 1 patient an X-inactivation analysis was performed to detect the X-inactivation ratio, as the percentage of cells tested in which each allele is active. RESULTS All the patients started suffering from night blindness in early childhood. Colour, fundus AF and OCT images showed the typical pattern of degeneration reported in men. One patient underwent retina implant surgery due to the severe atrophy. CONCLUSIONS This is a small selection of females with a severe phenotype that do not differ from the typical male phenotype. In our opinion gene therapy surgery should be warranted in this scenario.
Collapse
Affiliation(s)
- Anna Paola Salvetti
- Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, and Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Anika Nanda
- Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, and Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Robert E MacLaren
- Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, and Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom,
| |
Collapse
|
45
|
Ayachi S, Buscarlet M, Busque L. 60 Years of clonal hematopoiesis research: From X-chromosome inactivation studies to the identification of driver mutations. Exp Hematol 2020; 83:2-11. [PMID: 32001340 DOI: 10.1016/j.exphem.2020.01.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/18/2020] [Accepted: 01/22/2020] [Indexed: 12/17/2022]
Abstract
The history of clonal hematopoiesis (CH) research is punctuated by several seminal discoveries that have forged our understanding of cancer development. The clever application of the principle of random X-chromosome inactivation (XCI) in females led to the development of the first test to identify clonal derivation of cells. Initially limited by a low level of informativeness, the applicability of these assays expanded with differential methylation-based assays at highly polymorphic genes such as the human androgen receptor (HUMARA). Twenty years ago, the observation that skewing of XCI ratios increases as women age was the first clue that led to the identification of mutations in the TET2 gene in hematologically normal aging individuals. In 2014, large-scale genomic approaches of three cohorts allowed definition of CH, which was reported to increase the risk of developing hematologic cancers and cardiovascular diseases. These observations created a fertile field of investigation aimed at investigating the etiology and consequences of CH. The most frequently mutated genes in CH are DNMT3A, TET2, and ASXL1, which have a role in hematopoietic stem cell (HSC) development and self-renewal. These mutations confer a competitive advantage to the CH clones. However, the penetrance of CH is age dependent but incomplete, suggesting the influence of extrinsic factors. Recent data attribute a modest role to genetic predisposition, but several observations point to the impact of a pro-inflammatory milieu that advantages the mutated clones. CH may be a barometer of nonhealthy aging, and interventions devised at curbing its initiation or progression should be a research priority.
Collapse
Affiliation(s)
- Sami Ayachi
- Research Center, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada; Department of Medicine, Université de Montréal, Montreal, Québec, Canada
| | - Manuel Buscarlet
- Research Center, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada
| | - Lambert Busque
- Research Center, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada; Department of Medicine, Université de Montréal, Montreal, Québec, Canada; Hematology Division, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada.
| |
Collapse
|
46
|
Cho RY, Peñaherrera MS, Du Souich C, Huang L, Mwenifumbo J, Nelson TN, Elliott AM, Adam S, Eydoux P, Yang GX, Chijiwa C, Van Allen MI, Friedman JM, Robinson WP, Lehman A. Renpenning syndrome in a female. Am J Med Genet A 2019; 182:498-503. [PMID: 31840929 DOI: 10.1002/ajmg.a.61451] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 10/26/2019] [Accepted: 10/29/2019] [Indexed: 01/03/2023]
Abstract
Renpenning syndrome (OMIM: 309500) is a rare X-linked disorder that causes intellectual disability, microcephaly, short stature, a variety of eye anomalies, and characteristic craniofacial features. This condition results from pathogenic variation of PQBP1, a polyglutamine-binding protein involved in transcription and pre-mRNA splicing. Renpenning syndrome has only been reported in affected males. Carrier females do not usually have clinical features, and in reported families with Renpenning syndrome, most female carriers exhibit favorable skewing of X-chromosome inactivation. We describe a female with syndromic features typical of Renpenning syndrome. She was identified by exome sequencing to have a de novo heterozygous c.459_462delAGAG mutation in PQBP1 (Xp11.23), affecting the AG hexamer in exon 4, which is the most common causative mutation in this syndrome. Streaky hypopigmentation of the skin was observed, supporting a hypothesized presence of an actively expressed, PQBP1 mutation-bearing X-chromosome in some cells. X-inactivation studies on peripheral blood cells demonstrated complete skewing in both the proband and her mother with preferential inactivation of the maternal X chromosome in the child. We demonstrated expression of the PQBP1 mutant transcript in leukocytes of the affected girl. Therefore, it is highly likely that the PQBP1 mutation arose from the paternal X chromosome.
Collapse
Affiliation(s)
- Raymond Y Cho
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Maria S Peñaherrera
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Christele Du Souich
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Lijia Huang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jill Mwenifumbo
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tanya N Nelson
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Alison M Elliott
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Shelin Adam
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | -
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Patrice Eydoux
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Gui X Yang
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Chieko Chijiwa
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Margot I Van Allen
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Jan M Friedman
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Wendy P Robinson
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Anna Lehman
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.,BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| |
Collapse
|
47
|
Moyer AM, Matey ET, Miller VM. Individualized medicine: Sex, hormones, genetics, and adverse drug reactions. Pharmacol Res Perspect 2019; 7:e00541. [PMID: 31844524 PMCID: PMC6897337 DOI: 10.1002/prp2.541] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 10/08/2019] [Indexed: 12/16/2022] Open
Abstract
Clinically relevant adverse drug reactions differ between men and women. The underlying physiological and pharmacological processes contributing to these differences are infrequently studied or reported. As gene expression, cellular regulatory pathways, and integrated physiological functions differ between females and males, aggregating data from combined groups of men and women obscures the ability to detect these differences. This paper summarizes how genetic sex, that is, the presence of sex chromosomes XY for male or XX for female, and the influence of sex hormones affect transporters, receptors, and enzymes involved in drug metabolism. Changing levels of sex steroids throughout life, including increases at puberty, changes with pregnancy, and decreases with age, may directly and indirectly affect drug absorption, distribution, metabolism, and elimination. The direct and indirect effects of sex steroids in the form of exogenous hormones such as those used in hormonal contraceptives, menopausal hormone treatments, transgender therapy, and over-the-counter performance enhancing drugs may interfere with metabolism of other pharmaceuticals, and these interactions may vary by dose, formulation, and mode of delivery (oral, injection, or transdermal) of the steroid hormones. Few drugs have sex-specific labeling or dosing recommendations. Furthermore, there is limited literature evaluating how the circulating levels of sex steroids impact drug efficacy or adverse reactions. Such research is needed in order to improve the understanding of the impact of sex hormones on pharmacological therapies, particularly as medicine moves toward individualizing treatments.
Collapse
Affiliation(s)
- Ann M. Moyer
- Laboratory Medicine and PathologyMayo ClinicRochesterMNUSA
| | - Eric T. Matey
- Medical Therapy Management and Center for Individualized MedicineMayo ClinicRochesterMNUSA
| | - Virginia M. Miller
- Departments of Surgery, and Physiology and Biomedical EngineeringWomen's Health Research CenterMayo ClinicRochesterMNUSA
| |
Collapse
|
48
|
Fahim AT, Sullivan LS, Bowne SJ, Jones KD, Wheaton DKH, Khan NW, Heckenlively JR, Jayasundera KT, Branham KH, Andrews CA, Othman MI, Karoukis AJ, Birch DG, Daiger SP. X-Chromosome Inactivation Is a Biomarker of Clinical Severity in Female Carriers of RPGR-Associated X-Linked Retinitis Pigmentosa. Ophthalmol Retina 2019; 4:510-520. [PMID: 31953110 DOI: 10.1016/j.oret.2019.11.010] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/08/2019] [Accepted: 11/11/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE X-linked retinitis pigmentosa can manifest in female carriers with widely variable severity, whereas others remain unaffected. The contribution of X-chromosome inactivation (XCI) to phenotypic variation has been postulated but not demonstrated. Furthermore, the impact of genotype and genetic modifiers has been demonstrated in affected males but has not been well established in female carriers. The purpose of this study was to describe the scope of clinical phenotype in female carriers with mutations in RPGR and quantify the contribution of genotype, genetic modifiers, and XCI to phenotypic severity. DESIGN Cohort study. PARTICIPANTS Seventy-seven female carriers with RPGR mutations from 41 pedigrees. METHODS Coding single nucleotide polymorphisms were sequenced in candidate genetic modifier genes encoding known RPGR-interacting proteins. X-chromosome inactivation ratios were determined in genomic DNA isolated from blood (n = 42) and saliva (n = 20) using methylation status of X-linked polymorphic repeats. These genetic data were compared with disease severity based on quantitative clinical parameters. MAIN OUTCOME MEASURES Visual acuity, Humphrey visual field (HVF) results, full-field electroretinography results, and dark adaptation. RESULTS Most individuals at all ages were mildly affected or unaffected, whereas those who progressed to moderate or severe vision loss were older than 30 years. RPGR genotype was not associated with clinical severity. The D1264N variant in RPGRIP1L was associated with more severe disease. Skewed XCI toward inactivation of the normal RPGR allele was associated with more severe disease. The XCI ratio in both blood and saliva was a predictor of visual function as measured by HVF diameter, rod amplitude, flicker amplitude, and flicker implicit time. For carriers with extreme XCI skewing of 80:20 or more, 57% were affected severely compared with 8% for those with XCI of less than 80:20 (P = 0.002). CONCLUSIONS Female carriers with mutations in RPGR demonstrate widely variable clinical severity. X-chromosome inactivation ratios correlate with clinical severity and may serve as a predictor of clinically significant disease. Because RPGR gene therapy trials are underway, a future imperative exists to determine which carriers require intervention and when to intervene. X-chromosome inactivation analysis may be useful for identifying candidates for early intervention.
Collapse
Affiliation(s)
- Abigail T Fahim
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan.
| | - Lori S Sullivan
- Department of Genetics, University of Texas Health Science Center, Houston, Texas
| | - Sara J Bowne
- Department of Genetics, University of Texas Health Science Center, Houston, Texas
| | | | | | - Naheed W Khan
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan
| | - John R Heckenlively
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan
| | - K Thiran Jayasundera
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan
| | - Kari H Branham
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan
| | - Chris A Andrews
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan
| | - Mohammad I Othman
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan
| | - Athanasios J Karoukis
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan
| | | | - Stephen P Daiger
- Department of Genetics, University of Texas Health Science Center, Houston, Texas
| |
Collapse
|
49
|
Androgen Receptor Polymorphism and Female Sexual Function and Desire. J Sex Med 2019; 15:1537-1546. [PMID: 30415810 DOI: 10.1016/j.jsxm.2018.09.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 09/14/2018] [Accepted: 09/18/2018] [Indexed: 11/22/2022]
Abstract
INTRODUCTION The effect of testosterone depends on the exposure of and the sensitivity of the androgen receptor (AR). It has been shown that a cytosine-adenine-guanine (CAG) trinucleotide repeat polymorphism in the AR gene has an impact on AR functional capacity in men. However, large studies are lacking on the impact of this polymorphism on female sexual function. AIM To determine whether the CAG repeat length was associated with different aspects of women's sexual function and dysfunction, including desire, arousal, lubrication, orgasm, satisfaction, sexual pain, and sexually related personal distress. METHODS This cross-sectional study included 529 healthy women, aged 19-65 years. Participants completed a questionnaire to provide demographic and sexual data. The CAG repeat length was analyzed in a blood sample. The correlations between CAG repeat lengths and different aspects of sexual function were calculated. Independent Student t-tests were performed to evaluate differences in the mean number of CAG repeats in the short and long allele and of the biallelic mean length determined by simple calculation and X-inactivation analysis, respectively, between women with sexual problems and women without sexual problems. P values <.05 were considered statistically significant. MAIN OUTCOME MEASURE We used the Female Sexual Function Index, with 6 subdomains, to distinguish between women without and women with impaired sexual function; low sexual desire; impaired arousal, lubrication, or orgasm; diminished satisfaction; or pain during sex. The Female Sexual Distress Scale was used to measure sexually related personal distress. RESULTS Overall, we found that increasing numbers of CAG repeats were correlated to increased sexual function. We found that women with problems achieving orgasm had a significantly lower number of CAG repeats than women that reported no problems reaching orgasm. We found no associations between CAG repeat lengths and other aspects of female sexual dysfunction, including hypoactive sexual desire disorder. CLINICAL IMPLICATIONS The results could indicate an impact of the AR on women's sexual function, including the ability to reach orgasm. STRENGTH & LIMITATIONS This is a large study using validated sexual questionnaires. A limitation is the cross-sectional design. Owing to the study design, this study is explorative and hypothesis generating. CONCLUSION In this large cross-sectional study, we demonstrated that CAG repeat length is positively correlated to sexual function and that women with a reduced ability to reach orgasm had smaller numbers of CAG repeats in the AR gene than women with no orgasmic problems. These findings indicated that androgens and ARs might play a role in women's sexual function. Wåhlin-Jacobsen S, Flanagan JN, Pedersen AT, Kristensen E, Arver S, Giraldi A. Androgen Receptor Polymorphism and Female Sexual Function and Desire. J Sex Med 2018;15:1537-1546.
Collapse
|
50
|
Hagen LA, Arnegard S, Kuchenbecker JA, Gilson SJ, Neitz M, Neitz J, Baraas RC. The association between L:M cone ratio, cone opsin genes and myopia susceptibility. Vision Res 2019; 162:20-28. [PMID: 31254532 PMCID: PMC7122956 DOI: 10.1016/j.visres.2019.06.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 06/12/2019] [Accepted: 06/13/2019] [Indexed: 11/16/2022]
Abstract
In syndromic forms of myopia caused by long (L) to middle (M) wavelength (L/M) interchange mutations, erroneous contrast signals from ON-bipolar cells activated by cones with different levels of opsin expression are suggested to make the eye susceptible to increased growth. This susceptibility is modulated by the L:M cone ratio. Here, we examined L and M opsin genes, L:M cone ratios and their association with common refractive errors in a population with low myopia prevalence. Cycloplegic autorefraction and ocular biometry were obtained for Norwegian genetically-confirmed normal trichromats. L:M cone ratios were estimated from spectral sensitivity functions measured with full-field ERG, after adjusting for individual differences in the wavelength of peak absorption deduced from cone opsin genetics. Mean L:M cone ratios and the frequency of alanine at L opsin position 180 were higher in males than what has been reported in males in populations with high myopia prevalence. High L:M cone ratios in females were associated with lower degree of myopia, and myopia was more frequent in females who were heterozygous for L opsin exon 3 haplotypes than in those who were homozygous. The results suggest that the L:M cone ratio, combined with milder versions of L opsin gene polymorphisms, may play a role in common myopia. This may in part explain the low myopia prevalence in Norwegian adolescents and why myopia prevalence was higher in females who were heterozygous for the L opsin exon 3 haplotype, since females are twice as likely to have genetic polymorphisms carried on the X-chromosome.
Collapse
Affiliation(s)
- Lene A Hagen
- National Centre for Optics, Vision and Eye Care, Faculty of Health and Social Sciences, University of South-Eastern Norway, Hasbergs vei 36, 3616 Kongsberg, Norway.
| | - Solveig Arnegard
- National Centre for Optics, Vision and Eye Care, Faculty of Health and Social Sciences, University of South-Eastern Norway, Hasbergs vei 36, 3616 Kongsberg, Norway.
| | - James A Kuchenbecker
- Department of Ophthalmology, University of Washington Medical School, Box 358058, 750 Republican Street, Building E Room, Seattle, WA 98109, United States
| | - Stuart J Gilson
- National Centre for Optics, Vision and Eye Care, Faculty of Health and Social Sciences, University of South-Eastern Norway, Hasbergs vei 36, 3616 Kongsberg, Norway.
| | - Maureen Neitz
- Department of Ophthalmology, University of Washington Medical School, Box 358058, 750 Republican Street, Building E Room, Seattle, WA 98109, United States.
| | - Jay Neitz
- Department of Ophthalmology, University of Washington Medical School, Box 358058, 750 Republican Street, Building E Room, Seattle, WA 98109, United States.
| | - Rigmor C Baraas
- National Centre for Optics, Vision and Eye Care, Faculty of Health and Social Sciences, University of South-Eastern Norway, Hasbergs vei 36, 3616 Kongsberg, Norway.
| |
Collapse
|