Mutations in the DCHS1 Gene Cause Mitral Valve Prolapse in Humans

Ronen Durst ^1,2 David S Peal ³ Annemarieke deVlaming ⁵ Maire Leyne ² Michael Talkowski ² Maëlle Perrocheau Charles Simpson ² Christopher Jett ² Matthew R Stone ² Florie Charles ² Colby Chiang ² Jill A. Rosenfeld ¹² Xavier Jeunemaitre ^9,10 Albert Hagege ^9,10 Nabila Bouatia-Naji ⁹ Francesca N Delling ^2,7 Lisa A Freed ^2,8 Christian Dina ¹¹ Jean-Jacques Schott ¹¹ Kenneth D Irvine ⁶ Yaopan Mao ⁶ Kimberly Sauls ⁵ Andy Wessels ⁵ Tahirali Motiwala ⁵ Katherine Williams ⁵ Roger R. Markwald ⁵ Robert A Levine ^3,4 David J Milan ³ Russell A Norris ⁵ Susan A Slaugenhaupt ²

¹Cardiology, Hadassah Hebrew Universtiy Medical Center, Jerusalem
²Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
³Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, MA
⁴Cardiac Ultrasound Laboratory, Cardiology Division, Massachusetts General Hospital, Boston, MA
⁵Department of Regenerative Medicine and Cell Biology, College of Medicine, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, Charleston, SC
⁶Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, the State University of New Jersey, Piscataway, NJ
⁷Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Boston, MA
⁸Yale-New Haven Hospital Heart and Vascular Center, Yale School of Medicine, New Haven, CT
⁹INSERM, UMR-970, Paris Cardiovascular Research Center, Paris
¹⁰Faculty of Medicine, University Paris Descartes, Sorbonne Paris Cité, Paris
¹¹l’Institut du Thorax, 1Université de Nantes, Nantes
¹²Signature Genomic Laboratories, PerkinElmer, Spokane, WA

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.