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Mehta P, Vishvkarma R, Gupta S, Chattopadhyay N, Rajender S. Exome sequencing identified mutations in the WNT1 and COL1A2 genes in osteogenesis imperfecta cases. Mol Biol Rep 2024; 51:449. [PMID: 38536562 DOI: 10.1007/s11033-024-09326-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 02/07/2024] [Indexed: 04/11/2024]
Abstract
BACKGROUND Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone deformities, fractures and reduced bone mass. OI can be inherited as a dominant, recessive, or X-linked disorder. The mutational spectrum has shown that autosomal dominant mutations in the type I collagen-encoding genes are responsible for OI in 85% of the cases. Apart from collagen genes, mutations in more than 20 other genes, such as CRTAP, CREB3L1, MBTPS2, P4HB, SEC24D, SPARC, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1, TMEM38B, and IFITM5 have been reported in OI. METHODS AND RESULTS To understand the genetic cause of OI in four cases, we conducted whole exome sequencing, followed by Sanger sequencing. In case #1, we identified a novel c.506delG homozygous mutation in the WNT1 gene, resulting in a frameshift and early truncation of the protein at the 197th amino acid. In cases #2, 3 and 4, we identified a heterozygous c.838G > A mutation in the COL1A2 gene, resulting in a p.Gly280Ser substitution. The clinvar frequency of this mutation is 0.000008 (GnomAD-exomes). This mutation has been identified by other studies as well and appears to be a mutational hot spot. These pathogenic mutations were found to be absent in 96 control samples analyzed for these sites. The presence of these mutations in the cases, their absence in controls, their absence or very low frequency in general population, and their evaluation using various in silico prediction tools suggested their pathogenic nature. CONCLUSIONS Mutations in the WNT1 and COL1A2 genes explain these cases of osteogenesis imperfecta.
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Affiliation(s)
- Poonam Mehta
- Division of Endocrinology and Centre for ASTHI, CSIR-Central Drug Research Institute, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Rahul Vishvkarma
- Division of Endocrinology and Centre for ASTHI, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Sushil Gupta
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology and Centre for ASTHI, CSIR-Central Drug Research Institute, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Singh Rajender
- Division of Endocrinology and Centre for ASTHI, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Hu J, Lin X, Gao P, Zhang Q, Zhou B, Wang O, Jiang Y, Xia W, Xing X, Li M. Genotypic and Phenotypic Spectrum and Pathogenesis of WNT1 Variants in a Large Cohort of Patients With OI/Osteoporosis. J Clin Endocrinol Metab 2023; 108:1776-1786. [PMID: 36595228 PMCID: PMC10271228 DOI: 10.1210/clinem/dgac752] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 12/12/2022] [Accepted: 12/23/2022] [Indexed: 01/04/2023]
Abstract
CONTEXT Mutations in WNT1 can cause rare inherited disorders such as osteogenesis imperfecta (OI) and early-onset osteoporosis (EOOP). Owing to its rarity, the clinical characteristics and pathogenic mechanism of WNT1 mutations remain unclear. OBJECTIVE We aimed to explore the phenotypic and genotypic spectrum and treatment responses of a large cohort of patients with WNT1-related OI/OP and the molecular mechanisms of WNT1 variants. METHODS The phenotypes and genotypes of patients and their responses to bisphosphonates or denosumab were evaluated. Western blot analysis, quantitative polymerase chain reaction, and immunofluorescence staining were used to evaluate the expression levels of WNT1, total β-catenin, and type I collagen in the tibial bone or skin from one patient. RESULTS We included 16 patients with 16 mutations identified in WNT1, including a novel mutation. The types of WNT1 mutations were related to skeletal phenotypes, and biallelic nonsense mutations or frameshift mutations could lead to an earlier occurrence of fragility fractures and more severe skeletal phenotypes. Some rare comorbidities were identified in this cohort, including cerebral abnormalities, hematologic diseases, and pituitary adenoma. Bisphosphonates and denosumab significantly increased the spine and proximal hip BMD of patients with WNT1 mutations and reshaped the compressed vertebrae. We report for the first time a decreased β-catenin level in the bone of patient 10 with c.677C > T and c.502G > A compared to the healthy control, which revealed the potential mechanisms of WNT1-induced skeletal phenotypes. CONCLUSION Biallelic nonsense mutations or frameshift mutations of WNT1 could lead to an earlier occurrence of fragility fractures and a more severe skeletal phenotype in OI and EOOP induced by WNT1 mutations. The reduced osteogenic activity caused by WNT pathway downregulation could be a potential pathogenic mechanism of WNT1-related OI and EOOP.
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Affiliation(s)
- Jing Hu
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiaoyun Lin
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Peng Gao
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China
| | - Qian Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Bingna Zhou
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Ou Wang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yan Jiang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Weibo Xia
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiaoping Xing
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Mei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Panzaru MC, Florea A, Caba L, Gorduza EV. Classification of osteogenesis imperfecta: Importance for prophylaxis and genetic counseling. World J Clin Cases 2023; 11:2604-2620. [PMID: 37214584 PMCID: PMC10198117 DOI: 10.12998/wjcc.v11.i12.2604] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/18/2023] [Accepted: 03/27/2023] [Indexed: 04/25/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a genetically heterogeneous monogenic disease characterized by decreased bone mass, bone fragility, and recurrent fractures. The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature. The basic mechanism is a collagen-related defect, not only in synthesis but also in folding, processing, bone mineralization, or osteoblast function. In recent years, great progress has been made in identifying new genes and molecular mechanisms underlying OI. In this context, the classification of OI has been revised several times and different types are used. The Sillence classification, based on clinical and radiological characteristics, is currently used as a grading of clinical severity. Based on the metabolic pathway, the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches. Genetic classification has the advantage of identifying the inheritance pattern, an essential element for genetic counseling and prophylaxis. Although genotype-phenotype correlations may sometimes be challenging, genetic diagnosis allows a personalized management strategy, accurate family planning, and pregnancy management decisions including options for mode of delivery, or early antenatal OI treatment. Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches. This narrative review summarizes our current understanding of genes, molecular mechanisms involved in OI, classifications, and their utility in prophylaxis.
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Affiliation(s)
- Monica-Cristina Panzaru
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Andreea Florea
- Department of Medical Genetics - Medical Genetics resident, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Lavinia Caba
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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Zhu J, Liu K, He S, Yang Z, Song J, Ju Y, Xiong C, Zhang G, Yang W, Tang C. Type XV osteogenesis imperfecta: A novel mutation in the WNT1 gene, c.620G >A (p.R207H), is associated with an inner ear deformity. Intractable Rare Dis Res 2023; 12:58-61. [PMID: 36873675 PMCID: PMC9976088 DOI: 10.5582/irdr.2022.01099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/19/2022] [Accepted: 11/22/2022] [Indexed: 01/22/2023] Open
Abstract
The Wnt signaling pathway is vital in encouraging bone growth. WNT1 gene mutations have been identified as the major cause of type XV osteogenesis imperfecta (OI). Described here is a case of complex heterozygous WNT1 c.620G>A (p.R207H) and c.677C >T (p.S226L) OI caused by a novel mutation at locus c.620G >A (p.R207H). The female patient had type XV OI, distinguished by poor bone density, frequent fractures, a small stature, skull softening, lack of dentine hypoplasia, a brain malformation, and obvious blue sclera. A CT scan of the temporal bone revealed abnormalities of the inner ear, necessitating a hearing aid 8 months after birth. There was no family history of such disorders in the proband's parents. The proband inherited complex heterozygous WNT1 gene variants c.677C>T (p.S226L) and c.620G>A (p.R207H) from her father and mother, respectively. Presented here is a case of OI with inner ear deformation caused by c.620G>A (p.R207H), which is a novel WNT1 site mutation. This case broadens the genetic spectrum of OI and it provides a rationale for genetic testing of mothers and a medical consultation to estimate the risk of fetal illness.
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Affiliation(s)
- Jicai Zhu
- Department of Pediatrics, The First People's Hospital of Yunnan Province, Medical School & Affiliated Hospital, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Kai Liu
- Department of Pediatrics, The First People's Hospital of Yunnan Province, Medical School & Affiliated Hospital, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Shan He
- Department of Pediatrics, The First People's Hospital of Yunnan Province, Medical School & Affiliated Hospital, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Zihao Yang
- Medical School & Affiliated Hospital, Kunming University of Science and Technology. Department of Radiology, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Jiaying Song
- Medical School & Affiliated Hospital, Kunming University of Science and Technology. Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Yan Ju
- Medical School & Affiliated Hospital, Kunming University of Science and Technology. Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Caiyun Xiong
- Medical School & Affiliated Hospital, Kunming University of Science and Technology. Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Guomei Zhang
- Department of Pediatrics, The First People's Hospital of Yunnan Province, Medical School & Affiliated Hospital, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Wen Yang
- Medical School & Affiliated Hospital, Kunming University of Science and Technology. Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Chunhui Tang
- Department of Pediatrics, The First People's Hospital of Yunnan Province, Medical School & Affiliated Hospital, Kunming University of Science and Technology, Kunming, Yunnan, China
- Address correspondence to:Chunhui Tang, Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming 650021, Yunnan, China. E-mail:
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Campopiano MC, Fogli A, Michelucci A, Mazoni L, Longo A, Borsari S, Pardi E, Benelli E, Sardella C, Pierotti L, Dinoi E, Marcocci C, Cetani F. Case report: Early-onset osteoporosis in a patient carrying a novel heterozygous variant of the WNT1 gene. Front Endocrinol (Lausanne) 2022; 13:918682. [PMID: 36004351 PMCID: PMC9393300 DOI: 10.3389/fendo.2022.918682] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/14/2022] [Indexed: 12/02/2022] Open
Abstract
The WNT1 gene is crucial for bone development and homeostasis. Homozygous mutations in WNT1 cause severe bone fragility known as osteogenesis imperfecta type XV. Moreover, heterozygous WNT1 mutations have been found in adults with early-onset osteoporosis. We identified a 35 year-old Caucasian woman who experienced multiple vertebral fractures two months after her second pregnancy. There was no history of risk factors for secondary osteoporosis or family history of osteoporosis. Dual-energy X-ray absorptiometry confirmed a marked reduction of bone mineral density (BMD) at the lumbar spine (0.734 g/cm2, Z-score -2.8), femoral neck (0.48 g/cm2, Z-score -3.5), and total hip (0.589 g/cm2, Z-score -3.0). Blood tests excluded secondary causes of bone fragility. Genetic analysis revealed a heterozygous missense mutation (p.Leu370Val) in the WNT1 gene. Varsome classified it as a variant of uncertain significance. However, the fact that the Leucine residue at position 370 is highly conserved among vertebrate species and the variant has a very low allelic frequency in the general population would exclude the possibility of a polymorphism. The patient was treated for two years with teriparatide therapy associated with calcium and vitamin D supplements. During the follow-up period she did not report further clinical fractures. After 24 months of teriparatide, BMD increased at lumbar spine (+14.6%), femoral neck (+8.3%) and total hip (+4.9%) compared to baseline. We confirm that the heterozygous WNT1 mutation could cause a variable bone fragility and low turnover osteoporosis. We suggest that teriparatide is one of the most appropriate available therapies for this case.
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Affiliation(s)
- Maria Cristina Campopiano
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Antonella Fogli
- Laboratory of Molecular Genetics, University Hospital of Pisa, Pisa, Italy
| | - Angela Michelucci
- Laboratory of Molecular Genetics, University Hospital of Pisa, Pisa, Italy
| | - Laura Mazoni
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Antonella Longo
- Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, TX, United States
| | - Simona Borsari
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Elena Pardi
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Elena Benelli
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Chiara Sardella
- Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy
| | - Laura Pierotti
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Elisa Dinoi
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Claudio Marcocci
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
- Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy
| | - Filomena Cetani
- Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy
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Etich J, Rehberg M, Eckes B, Sengle G, Semler O, Zaucke F. Signaling pathways affected by mutations causing osteogenesis imperfecta. Cell Signal 2020; 76:109789. [PMID: 32980496 DOI: 10.1016/j.cellsig.2020.109789] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 12/17/2022]
Abstract
Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous connective tissue disorder characterized by bone fragility and skeletal deformity. To maintain skeletal strength and integrity, bone undergoes constant remodeling of its extracellular matrix (ECM) tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. There are at least 20 recognized OI-forms caused by mutations in the two collagen type I-encoding genes or genes implicated in collagen folding, posttranslational modifications or secretion of collagen, osteoblast differentiation and function, or bone mineralization. The underlying disease mechanisms of non-classical forms of OI that are not caused by collagen type I mutations are not yet completely understood, but an altered ECM structure as well as disturbed intracellular homeostasis seem to be the main defects. The ECM orchestrates local cell behavior in part by regulating bioavailability of signaling molecules through sequestration, release and activation during the constant bone remodeling process. Here, we provide an overview of signaling pathways that are associated with known OI-causing genes and discuss the impact of these genes on signal transduction. These pathways include WNT-, RANK/RANKL-, TGFβ-, MAPK- and integrin-mediated signaling as well as the unfolded protein response.
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Affiliation(s)
- Julia Etich
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, Frankfurt/Main, 60528, Germany.
| | - Mirko Rehberg
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany
| | - Beate Eckes
- Translational Matrix Biology, Faculty of Medicine, University of Cologne, Cologne 50931, Germany
| | - Gerhard Sengle
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne 50931, Germany; Cologne Center for Musculoskeletal Biomechanics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany
| | - Oliver Semler
- Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Center for Rare Diseases, University Hospital Cologne, University of Cologne, Cologne 50931, Germany
| | - Frank Zaucke
- Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital Friedrichsheim gGmbH, Frankfurt/Main, 60528, Germany
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