期刊
NATURE
卷 525, 期 7567, 页码 109-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nature14670
关键词
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资金
- Fondation Leducq (Paris, France) Mitral Transatlantic Network of Excellence grant [07CVD04]
- Innovation in Clinical Research award of the Doris Duke Charitable Foundation
- Aetna Quality Care Research Fund
- National Heart Lung and Blood Institute Resequencing and Genotyping (RSG) Service
- National Institutes of Health from the Extramural Research Facilities Program of the National Center for Research Resources [C06 RR018823]
- French Society of Cardiology
- National Heart Lung and Blood Institute [R01HL122906-01, R01-HL33756, COBRE 1P30 GM103342, 8P20 GM103444-07, R01-HL109004, R01-HL127692, RO1-HL095696]
- VA Merit Review [BX002327]
- National Institute of Mental Health [R00-MH095867]
- Hassenfeld Scholar Program
- March of Dimes
- M.G.H. Scholars Program
- American Heart Association [09GRNT2060075, 11SDG5270006, 2261354, 15GRNT25080052]
- National Science Foundation [EPS-0903795]
- NHLBI [K24 HL67434, R01HL72265, R01HL109506]
- Ellison Foundation, Boston, MA
- Howard Hughes Medical Institute
Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals(1-3). It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery(4,5). 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.
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