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Gene Discovered as Cause of Mitral Valve Prolapse

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    Although heart disease still represents the leading cause of death worldwide, genomic studies have increasingly helped scientists zero in on a number of likely causes. For example, mitral valve prolapse (MVP), which affects 2-3% of the population, has not been previously associated with a specific genetic mutation even though it was seen to occur frequently in certain families.

    Now, an international group led by researchers from the Massachusetts General Hospital (MGH) has identified the first gene in which mutations cause the most common form of MVP. The investigators reported finding a mutation within the DCHS1 gene among affected members of three families, where MVP was thought to be inherited.


    “This work 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,” explained senior author Susan Slaugenhaupt, Ph.D., scientific director of the MGH Research Institute and professor of Genetics at Harvard Medical School (HMS).

    The findings from this study were published recently in Nature through an article entitled “Mutations in DCHS1 cause mitral valve prolapse.”

    The mitral valve lies between the left atrium and the left ventricle and handles oxygenated blood returning from the lungs. The valve consists of two flaps that open to let blood pass through and close to keep it from flowing backwards. In MVP, the flaps become thickened, elongated, and lose their rigidity, preventing the valve from closing completely and allowing blood to leak backwards. Patients with serious MVP can develop shortness of breath, cardiac arrhythmia, heart failure, or an infection of the heart valves—making MVP the most common reason for mitral valve surgery.

    Using advanced diagnostic techniques, the investigators first linked the occurrence of MVP among the families to a genetic risk factor located on chromosome 11. Next a detailed DNA analysis of affected family members found two rare mutations in DCHS1.


    “This finding can teach us how to prevent this inborn disease from manifesting as an illness in people who inherit mutated forms of this gene,” stated co-author Robert Levine, M.D., professor of medicine at HMS and senior physician at the MGH Corrigan Minehan Heart Center. “Understanding how defects in this gene cause errors in early valve formation can point to ways we can prevent the progression of this condition to keep the valve and the heart healthy and help the patient avoid complications.”

    Additionally, the researchers did extensive studies in zebrafish and found that inactivation of the DCHS1 homolog led to significant developmental defects of the heart at the site corresponding to the mitral valve. The phenotype could be rescued through the introduction of a normal gene copy, but not a mutated version.

    “This discovery required the cooperation of multiple disciplines and teams—ranging from clinical cardiology and ultrasound diagnostics to classical genetics, screening of potential mutations in zebrafish and functional studies in our mouse models,” noted Dr. Levine.

    A major grant from the Leducq Foundation in Paris enabled the formation of a network consisting of 11 centers in the U.S. and four European countries, and analysis of DNA from those centers identified two French families in which MVP was caused by another DCHS1 mutation.

    “As a follow up, this same international network has been seeking other genes that cause MVP across the population, which should point us to common pathways that could be targets of therapies designed to prevent progression into symptomatic disease,” added co-author David Milan, M.D., assistant professor of medicine at HMS and assistant physician at the MGH Cardiovascular Research Center.

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