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Mutations in DCHS1 cause mitral valve prolapse.

ABSTRACT: Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1(+/-) mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1(+/-) mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.

SUBMITTER: Durst R

PROVIDER: S-EPMC4720389 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Mutations in DCHS1 cause mitral valve prolapse.

Durst Ronen R Sauls Kimberly K Peal David S DS deVlaming Annemarieke A Toomer Katelynn K Leyne Maire M Salani Monica M Talkowski Michael E ME Brand Harrison H Perrocheau Maëlle M Simpson Charles C Jett Christopher C Stone Matthew R MR Charles Florie F Chiang Colby C Lynch Stacey N SN Bouatia-Naji Nabila N Delling Francesca N FN Freed Lisa A LA Tribouilloy Christophe C Le Tourneau Thierry T LeMarec Hervé H Fernandez-Friera Leticia L Solis Jorge J Trujillano Daniel D Ossowski Stephan S Estivill Xavier X Dina Christian C Bruneval Patrick P Chester Adrian A Schott Jean-Jacques JJ Irvine Kenneth D KD Mao Yaopan Y Wessels Andy A Motiwala Tahirali T Puceat Michel M Tsukasaki Yoshikazu Y Menick Donald R DR Kasiganesan Harinath H Nie Xingju X Broome Ann-Marie AM Williams Katherine K Johnson Amanda A Markwald Roger R RR Jeunemaitre Xavier X Hagege Albert A Levine Robert A RA Milan David J DJ Norris Russell A RA Slaugenhaupt Susan A SA

Nature 20150810 7567

Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutati ...[more]

PMID: 26258302

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Project description:BackgroundInitial studies have suggested the familial clustering of mitral valve prolapse, but most of them were either community based among unselected individuals or applied non-specific diagnostic criteria. Therefore little is known about the familial distribution of mitral regurgitation in a referral-type population with a more severe mitral valve prolapse phenotype. The objective of this study was to evaluate the presence of familial mitral regurgitation in patients undergoing surgery for mitral valve prolapse, differentiating patients with Barlow's disease, Barlow forme fruste and fibro-elastic deficiency.MethodsA total of 385 patients (62 ± 12 years, 63% men) who underwent surgery for mitral valve prolapse were contacted to assess cardiac family history systematically. Only the documented presence of mitral regurgitation was considered to define 'familial mitral regurgitation'. In the probands, the aetiology of mitral valve prolapse was defined by surgical observations.ResultsA total of 107 (28%) probands were classified as having Barlow's disease, 85 (22%) as Barlow forme fruste and 193 (50%) patients as fibro-elastic deficiency. In total, 51 patients (13%) reported a clear family history for mitral regurgitation; these patients were significantly younger, more often diagnosed with Barlow's disease and also reported more sudden death in their family as compared with 'sporadic mitral regurgitation'. In particular, 'familial mitral regurgitation' was reported in 28 patients with Barlow's disease (26%), 15 patients (8%) with fibro-elastic deficiency and eight (9%) with Barlow forme fruste (P < 0.001).ConclusionsIn a large cohort of patients operated for mitral valve prolapse, the self-reported prevalence of familial mitral regurgitation was 26% in patients with Barlow's disease and still 8% in patients with fibro-elastic deficiency, highlighting the importance of familial anamnesis and echocardiographic screening in all mitral valve prolapse patients.

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Mutations in DCHS1 cause mitral valve prolapse.

Publications

Mutations in DCHS1 cause mitral valve prolapse.

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