Novel insertion mutation (Arg1822_Glu1823dup) in MYH6 coiled-coil domain causing familial atrial septal defect |
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| Institution: | 1. Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China;2. The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China;3. Prenatal Diagnosis Center, Guangdong Provincial People''s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China;4. Department of Obstetrics and Gynecology, Guangdong Provincial People''s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China;5. Department of Cardiovascular Surgery of Guangdong Provincial Cardiovascular Disease Institute, Guangdong Provincial People''s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China;6. Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People''s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China;7. Research Department of Medical Sciences, Guangdong Provincial People''s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China;1. Institute for Human Genetics, University Hospital Essen, Germany;2. Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany;3. Cologne Center for Genomics, University of Cologne, Cologne, Germany;4. Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey;5. Eastern Mediterranean University School of Medicine, Cyprus, Mersin, 10, Turkey;6. Cluster of Excellence „Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany;7. Center for Human Genetics, and Department of Human Genetics, University of Regensburg, Regensburg, Germany;8. Department of Pediatrics, Neonatology, University Hospital Essen, Germany;9. Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Essen, Germany, University Hospital Essen, Germany;10. Department of Obstetrics and Gynaecology, University Hospital Essen, University Duisburg-Essen, Essen, Germany;1. Paediatric Medicine, KK Women''s and Children''s Hospital, Singapore;2. Dermatology Service, KK Women''s and Children''s Hospital, Singapore;3. SingHealth Duke-NUS Paediatric Academic Medicine Programme, Singapore;4. Research Laboratory, KK Women''s and Children''s Hospital, Singapore;5. Clinical Translational Research, Singapore General Hospital, Singapore;1. Laboratory of Human Cytogenetics, Molecular Genetics and Biology of Reproduction, Farhat Hached University Teaching Hospital, Sousse, Tunisia;2. Higher Institute of Biotechnology of Monastir, University of Monastir, Monastir, Tunisia;3. Pediatric Department, Farhat Hached University Teaching Hospital, Sousse, Tunisia;4. Human Developmental Genetics Unit, Institut Pasteur, Paris, France;5. Faculty of Medicine, Sousse University, Tunisia;1. Dpt. of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Denmark;2. Dpt. of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom;3. National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom;4. Dpt. of Pediatric Pulmonary Medicine, University Hospital of Copenhagen, Denmark;5. Section for Lung Transplantation, Dpt. of Cardiology, University Hospital of Copenhagen, Rigshospitalet, Denmark;6. Dpt. of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark;7. Dpt. of Dermatology, University Hospital of Copenhagen, Bispebjerg Hospital, Denmark |
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| Abstract: | ObjectiveAtrial septal defect, secundum (ASD Ⅱ, OMIM: 603642) is the second common congenital heart defect (CHD) in China. However, the genetic etiology of familial ASD II remains elusive.Methods and resultsUsing whole-exome sequencing (WES) and Sanger sequencing, we identified a novel myosin heavy chain 6 (MYH6) gene insertion variation, NM_002471.3: c.5465_5470dup (Arg1822_Glu1823dup), in a large Chinese Han family with ASD II. The variant Arg1822_Glu1823dup co-segregated with the disease in this family with autosomal dominant inheritance. The insertion variant located in the coiled-coil domain of the MYH6 protein, which is highly conserved across homologous myosin proteins and species. In transfected myoblast C2C12 cell lines, the MYH6 Arg1822_Glu1823dup variant significantly impaired myofibril formation and increased apoptosis but did not significantly reduce cell viability. Furthermore, molecular simulations revealed that the Arg1822_Glu1823dup variant impaired the myosin α-helix, increasing the stability of the coiled-coil myosin dimer, suggesting that this variant has an effect on the coiled-coil domain self-aggregation. These findings indicate that Arg1822_Glu1823dup variant plays a crucial role in the pathogenesis of ASD II.ConclusionOur findings expand the spectrum of MYH6 variations associated with familial ASD II and may provide a molecular basis in genetic counseling and prenatal diagnosis for this Chinses family. |
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| Keywords: | Atrial septal defect Myofibril formation Apoptosis Whole exome sequencing |
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