As part of a multi-center investigation recently reported in the journals Nature1 and Nature Genetics,2 researchers at the Medical University of South Carolina (MUSC) and Harvard/Massachusetts General Hospital as well as other international institutes have discovered genetic and biological causes for MVP. The investigators identify that MVP can be a result of heritable genetic errors that occur during embryonic cardiac development and progress over the lifespan of affected individuals.
Mitral valve prolapse (MVP) affects 1 in 40 individuals making it one of the most prevalent human diseases. Many individuals with MVP develop potentially life-threatening cardiac arrhythmia and heart failure.
In MVP, one or both flaps of the mitral valve bulge backward into the left atrium causing it to close improperly upon termination of atrial systole. Mitral valve prolapse is often detected as a heart murmur and is usually asymptomatic, but in roughly 10% of cases mitral valve regurgitation intensifies to a clinically severe stage. In severe cases, arrhythmic heartbeats develop, which increases the risk of stroke, heart failure and sudden cardiac death. In fact, the risks are high enough in MVP to make it the leading indication for mitral valve surgery.
In the Nature article,1 investigators used linkage analyses and capture sequencing technology to examine protein-coding genes on chromosome 11 in four members of a large family segregating non-syndromic MVP. They discovered a missense mutation in the DCHS1 gene, which codes for the protein dachsous homolog 1, a member of the calcium-dependent cell-cell adhesion family of cadherins. Another DCHS1 mutation was found in additional families segregating deleterious MVP. Both mutations reduce DCHS1 protein stability in mitral valve interstitial cells (MVICs), a finding corroborated with the discovery of the original mutation in MVICs in a human patient with MVP that underwent mitral valve repair surgery. Dchs1 mutant mice displayed similar pathology, along with scattered migration of MVICs during growth, suggesting that protein stability is essential to maintaining cues for cell polarity during mitral valve development.
In a subsequent manuscript published in Nature Genetics,2 the investigators performed a genome-wide association study (GWAS) to identify genetic variants in a population of more than 10,000 subjects. Single nucleotide variants (SNPs) with genome-wide significance were identified in the patient cohorts and genes surrounding these SNPs were functionally evaluated in multiple in vivo models.
The results from both studies highlight a potential unifying biological cause for MVP in the population.
“We have found a genetic and biological reason for one of the most common diseases affecting the human population," says MUSC researcher Russell A. (Chip) Norris, Ph.D., who was a co-senior author on the studies. "This is a critical initial step as we transform this discovery into new remedial therapies to treat the disease.” Roger R. Markwald, Ph.D., and Andy Wessels, Ph.D. both of the Department of Regenerative Medicine and Cell Biology at MUSC, were also co-authors.
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1 Durst, et al. Mutations in DCHS1 cause mitral valve prolapse. Nature. 2015 Aug 10 [Epub ahead of print]. Available at http://dx.doi.org/10.1038/nature14670