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Study Links Rare Mutations in Cadherin Gene to Mitral Valve Prolapse

NEW YORK (GenomeWeb) – An international team led by investigators at Massachusetts General Hospital described mutations in a cadherin-coding gene, DCHS1, that are capable of causing a heart disease called mitral valve prolapse.

As they reported today in Nature, the researchers did targeted sequencing on four members of a family affected by non-syndromic mitral valve prolapse, focusing on a chromosome 11 region implicated in a previous study.

The search led to missense mutations in DCHS1 that were subsequently shown to diminish the stability of the resulting protein in follow-up experiments on mouse and zebrafish models or mitral valve interstitial cells from patients who'd undergone surgery to repair mitral valve problems.

The finding "provides insights into the pathways regulating valve growth and development and implicates a previously unrecognized basis for the long-term structural integrity of the mitral valve," co-senior author Susan Slaugenhaupt, a researcher with Mass General's Center for Human Genetic Research and scientific director of the MGH Research Institute, said in a statement.

"[D]iscovery of this novel mechanistic pathway elucidated by intensively studying rare familial mutations will facilitate the identification of additional [mitral valve prolapse] genes," she and her co-authors wrote, "and reveal pathogenic mechanisms that hold the potential for pre-surgical therapy for this very common cardiac disease."

Mitral valve prolapse is a heart condition characterized by thickening and stretching of part of the valve that regulates blood flow between the heart's left atrium and its left ventricle. This irregularity interferes with proper closure of the valve and can allow blood to trickle back in the wrong direction — a situation known as mitral regurgitation that contributes to further complications such as infection, arrhythmia, shortness of breath, and so on.

At the moment, mitral regurgitation is typically treated with surgery, though researchers speculated that by more clearly defining the causes of mitral valve prolapse, it might eventually be possible to tackle the disease at an earlier stage before severe symptoms develop.

Following from a past linkage analysis implicating a region on chromosome 11 in a family affected by non-syndromic mitral valve prolapse, the team used tiled capture and Illumina sequencing to sequence that region in four affected members of the family.

Among the almost 4,900 SNPs and/or small insertions or deletions detected in the region, the researchers noted that all of the affected family members carried rare, missense mutations in DCHS1.

When they scoured exome sequences generated for 21 individuals from France with early onset mitral valve prolapse who were enrolled through the Leducq Mitral Network, the researchers found two more families affected by another loss-of-function glitch in DCHS1.

And through a series of experiments in zebrafish, mice, and cell lines, they demonstrated that mutations in — or missing copies of — the DCHS1 gene can cause lower-than-usual DCHS1 protein levels and cardiac phenotypes that resemble mitral valve prolapse.