ZFIN ID: ZDB-PUB-150825-48
Genetic association analyses highlight biological pathways underlying mitral valve prolapse
Dina, C., Bouatia-Naji, N., Tucker, N., Delling, F.N., Toomer, K., Durst, R., Perrocheau, M., Fernandez-Friera, L., Solis, J., PROMESA investigators, Le Tourneau, T., Chen, M.H., Probst, V., Bosse, Y., Pibarot, P., Zelenika, D., Lathrop, M., Hercberg, S., Roussel, R., Benjamin, E.J., Bonnet, F., Lo, S.H., Dolmatova, E., Simonet, F., Lecointe, S., Kyndt, F., Redon, R., Le Marec, H., Froguel, P., Ellinor, P.T., Vasan, R.S., Bruneval, P., Markwald, R.R., Norris, R.A., Milan, D.J., Slaugenhaupt, S.A., Levine, R.A., Schott, J.J., Hagege, A.A., Mvp-France, Jeunemaitre, X., Leducq Transatlantic MITRAL Network
Date: 2015
Source: Nature Genetics   47(10): 1206-11 (Journal)
Registered Authors: Milan, David J.
Keywords: none
MeSH Terms:
  • Animals
  • Case-Control Studies
  • Genome-Wide Association Study
  • Humans
  • Mice
  • Mitral Valve Prolapse/genetics*
PubMed: 26301497 Full text @ Nat. Genet.
Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. 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 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 Tns1(-/-) 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.