Journal
NATURE GENETICS
Volume 47, Issue 10, Pages 1206-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3383
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Funding
- Nantes Hospital (CHU Nantes)
- US National Institutes of Health (NIH) [K24 HL67434, R01 HL72265, HL109506]
- French young investigator fund [ANR-13-ISV1-0006-0]
- Hassenfeld Scholar Program
- NIH [HL092577, HL104156, K24HL105780, HL065962]
- American Heart Association [13EIA14220013, 15GRNT25080052]
- Fondation Leducq [14CVD01]
- Canadian Institutes of Health Research (CIHR) [MOP-102737, MOP-114997, MOP-126072]
- Fonds de recherche Quebec-Sante (FRQS)
- CIHR [MOP-102481, MOP-137058]
- Spanish Society of Cardiology
- fund for medical discovery of the Massachusetts General Hospital
- European Commission
- US National Institutes of Health [C06 RR018823]
- Extramural Research Facilities Program of the Heart, Lung, and Blood Institute [R01-HL33756, COBRE 1P30 GM103342, 8P20 GM103444-07, R01-HL127692]
- INSERM
- French Society of Cardiology
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Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death(1). Previous family and pathophysiological studies suggest a complex pattern of inheritance(2-5). We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor(6) and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns(1-/-) mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair(7).
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