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Nature. 2015 Sep 3;525(7567):109-13. doi: 10.1038/nature14670. Epub 2015 Aug 10.

Mutations in DCHS1 cause mitral valve prolapse.

Author information

1
Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA.
2
Cardiology Division, Hadassah Hebrew University Medical Center, POB 12000 Jerusalem, Israel.
3
Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Department of Medicine, Children's Research Institute, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425, USA.
4
Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
5
Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
6
INSERM, UMR-970, Paris Cardiovascular Research Center, 75015 Paris, France.
7
Université Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, 75006 Paris, France.
8
Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
9
Yale-New Haven Hospital Heart and Vascular Center, Yale School of Medicine, 20 York Street, New Haven, Connecticut 06510, USA.
10
Department of Cardiology, University Hospital Amiens; INSERM U-1088, Jules Verne University of Picardie, 80000 Amiens, France.
11
Inserm U1087; Institut du Thorax; University Hospital, 44007 Nantes, France.
12
Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), 28029 Madrid, Spain.
13
Hospital Universitario Monteprincipe, 28660 Madrid, Spain.
14
Genetic Causes of Disease Group, Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain.
15
Universitat Pompeu Fabra (UPF), 08002 Barcelona, Catalonia, Spain.
16
Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Catalonia, Spain.
17
CIBER in Epidemiology and Public Health (CIBERESP), 08036 Barcelona, Catalonia, Spain.
18
Genomic and Epigenomic Variation in Disease Group, Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain.
19
CNRS, UMR 6291, 44007 Nantes, France.
20
Université de Nantes, 44322 Nantes, France.
21
CHU Nantes, l'Institut du Thorax, Service de Cardiologie, 44093 Nantes, France.
22
Service d'Anatomie Pathologique, Hôpital Européen Georges Pompidou, 75015 Paris, France.
23
National Heart and Lung Institute, Harefield, Heart Science Centre, Imperial College London, London SW7 2AZ, UK.
24
Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, USA.
25
INSERM UMR_S910, Team physiopathology of cardiac development Aix-Marseille University, Medical School La Timone, 13885 Marseille, France.
26
Department of Cellular and Molecular Biology, University of Texas Health Science Center Northeast Tyler, Texas75708, USA.
27
Gazes Cardiac Research Institute, Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
28
Department of Radiology and Radiological Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
29
Assistance Publique - Hôpitaux de Paris, Département de Génétique, Hôpital Européen Georges Pompidou, 75015 Paris, France.
30
Assistance Publique - Hôpitaux de Paris, Département de Cardiologie, Hôpital Européen Georges Pompidou, 75015 Paris, France.
31
Cardiac Ultrasound Laboratory, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.

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.

PMID:
26258302
PMCID:
PMC4720389
DOI:
10.1038/nature14670
[Indexed for MEDLINE]
Free PMC Article

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