MItral Valve Disease: From Genetics to Mechanisms and Improved CARE – I-CARE

Mitral valve prolapse (MVP) is a common cardiac valve disease. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic etiology leading to non-syndromic MVP has remained elusive. Autosomal dominant familial MVP has been linked to chromosomes 16, 11 and 13 in several families . The initial discovery of filamin A mutations in X-linked mitral and aortic valve dystrophy by Partner 1 (Kyndt, Circulation, 2007) raises intriguing questions of how a cytostructural defect alters interstitial cell and matrix biology. In 2015, using whole-exome and targeted sequencing, we have identified loss-of-function mutations in the DCHS1 gene which encodes a member of the cadherin superfamily, in multigenerational pedigrees with MVP. Functional and mechanistic data suggest that DCHS1 plays a vital role during valve morphogenesis and that its disruption results in cell alignment defects in the developing mitral leaflets (Ronen, Nature, 2015). Furthermore we also investigated the role of common genetic variants predisposing to MVP in large clinical cohorts. By a genome-wide association study, we have discovered six loci associated to MVP in the general population. At one locus, we showed that the focal adhesion protein tensin1 (TNS), which is involved in cytoskeleton organization, plays a role in valve development in zebrafish and mouse and may be regulated by a distant enhancer where genetic variants increase the risk of MVP in humans. In line with the involvement of the actin-binding protein Filamin A (FLNA), this study reinforces the concept that proper cytoskeleton organization is underlying normal and pathological mitral valve development (Dina, Nat Genet. 2015).

Altogether these recent findings have highlighted a strong genetic component for MVP reinforcing the concept that valve degeneration is not solely related to aging and opens new fields of investigation in cardiac valve disease. There is strong evidence for high genetic heterogeneity in mitral valve disease. Better characterizing the complex interplay between rare and common genetic variant will help in further understanding the pathophysiology of this valve disorder.

Here we aim to establish a new collaborative translational research program as a follow up of a previous Transatlantic Leducq Network focused on mitral valve disease.

More specifically we plan to further investigate the genetic basis of valve degeneration through an integrated research program combining high-throughput genetic screening and functional investigations. We will develop two complementary approaches:
1. Genetic investigations to further address the heart valve biology
• Identify new MVP-susceptibility genes and estimate their relative roles in the burden of severe clinical forms of MVP.
• Pursue the GWAS-based investigation to identify additional loci to better understand the contribution of common genetic variants in MVP risk. More specifically, we will investigate the molecular mechanisms underlying the most interesting association signal and best candidate gene in the TNS locus and follow-up our discovery efforts by investigating more deeply existing and upcoming GWAS meta-analyses with promising association signals.
2. Improve therapeutic application by developing a translational project aiming to characterize:
• Early biomarkers for this severe degenerative disease
• New clinical / echocardiographic criteria to identify patients at risk, in conjunction or independently of the genetic background, and prevent MVP complications.
This project will be accomplished by applying state-of-the-art methods of molecular genetics, bioinformatics, cell biology and advanced MVP imaging. All partners have demonstrated in the past their ability to successfully conduct similar research programs. Most importantly this project relies on existing cohorts of patients and on existing networks as well as on preliminary data.