Abstract
Nonsyndromic mitral valve prolapse (MVP) is a common degenerative valvulopathy of unknown aetiology that predisposes to heart failure and sudden death. Here we investigate functional evidence for candidate genes near genome-wide association study (GWAS) loci to understand the mechanisms underlying the genetic susceptibility to MVP. To prioritize genes, we used literature and databases (e. g ENCODE, eQTLs). We analysed the expression pattern of 3 candidate genes during valve development in mouse embryos by immunohistochemistry (IHC) i) completion of endothelial-to-mesenchymal transformation (E13.5), ii) valve sculpting and elongation (E17.5) and iii) adult form (9 months). Morpholino knockdown (KD) was performed for 8 genes in zebrafish and assayed the function of developing atrioventrocular (AV) canal by scoring the embryos according to the presence of erythrocyte regurgitation. On chr3, the association is in an intron of LMCD1, a repressor of GATA6 previously implicated in cardiac hypertrophy. KD of Lmcd1 in zebrafish resulted in a significant atrioventricular valve defect with regurgitation. On Chr2, the associated variants were upstream to TNS1 encoding a focal adhesion and actin-interacting protein. Tensin1 is expressed during valve morphogenesis in mice and maintained in the adult endothelial and valvular interstitial cells. Hematoxylin and eosin histological staining in 9-month Tns1-/- mice show enlarged posterior mitral leaflets with myxomatous aspects. In addition, zebrafish KD of Tns1 induced AV regurgitation. The functional validation of genes located in or near MVP susceptibility loci identifies new MVP mechanisms and stresses the role of cytoskeleton integrity in valve development. This study reveals LMCD1 and TNS1 at play as early as during valve development and can potentially be targeted during adulthood to improve the natural history of MVP.
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