Mutations in the DCHS1 Gene Cause Mitral Valve Prolapse In Humans. R. Durst1,2, DS. Peal3, A. deVlaming4, M. Leyne1, M. Talkowski1, M. Perrocheau5, C. Jett1, C. Simpson1, MR. Stone1, F. Charles1, C. Chiang1, JA. Rosenfeld11, X. Jeunemaitre5,6,7, A. Hagege6,7,8, N. Bouatia-Naji5,6, FN. Delling12, LA. Freed13, C. Dina9, 14, 15, JJ. Schott9, 14, 15, KD. Irvine10, Y. Mao10, K. Sauls4, A. Wessels4, T. Motiwala4, K. Williams4, RR. Markwald4, RA. Levine3,16, DJ. Milan3, RA. Norris4, SA. Slaugenhaupt1 1) Center for Human Genetic Research, Massachusetts General Hospital and Department of Neurology, Harvard Medical School, 185 Cambridge St., Boston, MA 02114 USA; 2) Cardiology Division, Hadassah Hebrew University Medical Center, Jerusalem, Israel, POB 12000; 3) Cardiovascular Research Center, Cardiology Division, Harvard Medical School and Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114 USA; 4) Department of Regenerative Medicine and Cell Biology, School of Medicine, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USA; 5) 10INSERM, UMR-970, Paris Cardiovascular Research Center, 75015 Paris, France; 6) University Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, 75006 Paris, France; 7) Assistance Publique - Hôpitaux de Paris, Cardiology Department, Hopital EuropeenEuropéen Georges Pompidou, 75015, Paris, France; 8) INSERM, UMR-970 633, Paris Cardiovascular Research Center, 75015 Paris, France; 9) INSERM, UMR1087, lInstitut du Thorax, Nantes, France; CNRS, UMR6291, Nantes, France; 10) Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, the State University of New Jersey, Piscataway NJ 08854 USA; 11) Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA; 12) Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; 13) Yale-New Haven Hospital Heart and Vascular Center, Yale School of Medicine, 20 York Street, New Haven, CT 06510 USA; 14) Université de Nantes, Nantes, France; 15) CHU Nantes, lInstitut du Thorax, France; 16) Cardiac Ultrasound Laboratory, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114 USA.

   Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. MVP can manifest clinically as mitral regurgitation and lead to arrhythmia, heart failure, and sudden death. Despite a clear heritable component, the genetic etiology and the defective developmental pathways that lead to MVP have remained elusive. A large multigenerational family segregating non-syndromic MVP was linked to chromosome 11 and DNA sequencing of the candidate region was performed on four affected family members. We report a genetic variant in the DCSH1 gene as a genetic risk factor for non-syndromic MVP in humans. Morpholino knock-down of the zebrafish homologue of DCHS1 results in a disruption of the atrioventricular constriction that is not rescued by the human mutation. Loss of function studies in Dchs1 knockout mice result in a mitral valve-specific valvulopathy characterized by a myxomatous phenotype with leaflet elongation and thickening in adults. This adult pathology was traced back to developmental errors in interstitial cell alignment during valve morphogenesis. DCHS1 haploinsufficiency, resulting from decreased stability of the mutant protein, leads to non-syndromic MVP in a large pedigree. Evaluation of mice heterozygous for Dchs1 loss demonstrates that disruption of interstitial cell alignment during valve morphogenesis can result in a myxomatous valvulopathy in adults, implicating a previously unrecognized paradigm in valve development in the long-term structural integrity of the mitral valve.

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