Novel missense loss-of-function mutations of WNT1 in an autosomal recessive Osteogenesis imperfecta patient |
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| Affiliation: | 1. Department of Biological Sciences, Sookmyung Women''s University, Seoul 04310, Republic of Korea;2. Department of Orthopaedic Surgery, Korea University Anam Hospital, Seoul, Republic of Korea;3. Division of Pediatric Orthopaedics, Seoul National University Children''s Hospital, Seoul, Republic of Korea;4. Research Center for Cell Fate Control, Sookmyung Women''s University, Seoul 04310, Republic of Korea;1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea;2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea;3. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-Si, Gyeonggi-Do, Republic of Korea;4. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea;1. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain;2. Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain;3. Neurology Service, Son Espases University Hospital, Mallorca, Spain;4. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain;5. Parkinson''s disease and Movement Disorders Unit, Neurology Service, Institut Clinic de Neurociencies, Hospital Clinic de Barcelona, Barcelona;6. Department of Pharmacology, University of Extremadura, Cáceres, Spain;7. Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain;8. Movement Disorders Unit, Department of Neurology, Sant Pau Hospital, Autonomous University of Barcelona, Catalonia, Spain;9. Neurology Department, Institut d''Investigacions Biomediques Sant Pau, Hospital de Sant Pau, Universitat Autónoma de Barcelona, Barcelona, Spain;10. Department of Biochemistry and Molecular Biology, University of Extremadura, Cáceres, Spain;1. Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, South Korea;2. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea;3. Infection Control Office, Inje University Sanggye Paik Hospital, Seoul, South Korea;4. Department of Infectious Diseases, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea;5. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea;6. Department of Nursing, Soonchunhyang University College of Medicine, Cheonan, South Korea;7. Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, South Korea;8. Infection Control Office, Korea University Guro Hospital, Seoul, South Korea;9. Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, South Korea;10. Department of Infection Control, Kyunghee University Hospital, Seoul, South Korea;11. Division of Infectious Disease Control, Korea Centres for Disease Control and Prevention, Osong, South Korea;1. Department of Thoracic and Cardiovascular Surgery, Hanseo Hospital, Busan;2. Department of Thoracic and Cardiovascular Surgery, Kangwon National University Hospital, Chuncheon-si, Gangwon-do;3. Department of Thoracic and Cardiovascular Surgery, Sejong General Hospital, Bucheon-si, Gyeonggi-do;4. Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul, Korea |
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| Abstract: | Osteogenesis imperfecta (OI) is a heritable skeletal disorder characterized by bone fragility and low bone mass. Recently, loss-of-function mutations of WNT1 have been reported to be causative in OI or osteoporosis. We report an OI patient with novel compound heterozygous WNT1 missense mutations, p.Glu123Asp and p.Cys153Gly. Both mutations are found in the exon 3, and the p.Glu123Asp is the most proximal N-terminus missense mutation among the reported WNT1 missense mutations in OI patients. In vitro functional analysis reveals that while expression of wildtype WNT1 stimulates canonical WNT1-mediated β-catenin signaling, that of individual WNT1 mutant fails to do so, indicative of the pathogenic nature of the WNT1 variants. Although the pathogenic mechanism of WNT1 defects in OI has yet to be uncovered, these findings further contribute to the implications and importance of functional relevance of WNT1 in skeletal disorders. |
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| Keywords: | Osteogenesis imperfecta Loss-of-function mutation |
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