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Scientists Identify First Gene for Most Common Form of Mitral Valve Prolapse

Research on the DNA of a large multi-generational family has provided a genetic clue that enabled scientists to pinpoint a gene that plays a role in mitral valve prolapse (MVP), a common cardiac disease that is the leading cause of heart valve surgery, according to a study presented today (Thursday, October 24) at the American Society of Human Genetics (ASHG) 2013 meeting in Boston. MVP affects 2.5% of the population and typically presents symptoms in adulthood, often leading to heart failure. 15% of the patients inherit the disease, but the remaining 85% of MVP incidence is sporadic. The scientists who located the gene, named DCSH1 (from the dachsous1 gene in Drosophila), also determined how mutations in this gene disrupt the normal embryonic development of the mitral valve, one of the valves that controls blood flow in the heart. “This work provides insights into the pathways regulating valve growth and development,” said Susan Slaugenhaupt, Ph.D., Professor of Neurology in the Center for Human Genetic Research at Massachusetts General Hospital (MGH) and Harvard Medical School and one of the lead scientists in the collaborative group that conducted the research. “The results implicate a previously unrecognized paradigm in the development of long-term structural integrity in the mitral valve,” said Ronen Y. Durst, M.D., former member of Dr. Slaugenhaupt’s lab and now a senior cardiologist at Hebrew University and Hadassah Medical Center in Jerusalem. Dr. Durst presented the study this afternoon at ASHG 2013. The researchers’ first step was to link MVP to a region on human chromosome 11 in the DNA of the group of relatives with the heart disorder. By sequencing that DNA region in family members, the scientists were able to link mutations in DCSH1 to MVP. To understand the normal biological functions altered by the mutated copy of DCSH1, the researchers turned to two animal models, zebrafish and mice. Experimentally reducing the expression level of the zebrafish version of DCSH1 resulted in abnormal heart development. “Treating the zebrafish embryos with the normal copy of the DCHS1 gene rescued the lesion, while the mutated human DCHS1 gene did not,” said Dr. Slaugenhaupt. “This finding constitutes strong evidence that the mutation disrupts the normal function of DCHS1.” To begin to understand the normal function of DCHS1 in the valve, the researchers obliterated, or knocked out, one of the corresponding genes in mice. The heterozygous mice were born with excessive connective tissue in the mitral valve that was elongated, thickened, and the valve prolapsed into the left atrium, as in the human disease. The scientists then traced the excessive connective tissue to developmental errors in the alignment of interstitial cells responsible for proper heart valve development and growth. “These developmental errors cause mitral valve prolapse and regurgitation in adult mice,” said Dr. Slaugenhaupt. DCHS1 is the first gene implicated in the most common form of MVP, which is not associated with other syndromes. MVP is the most common indication for surgical intervention to repair the mitral valve. Dr. Slaugenhaupt said that the research was an interdisciplinary collaboration among scientists specializing in human genetics, cardiac imaging (Robert Levine, M.D., Senior Physician, Cardiac Ultrasound Laboratory, MGH), zebrafish modeling (David Milan, M.D., Cariologist and Cardiac Electrophysiologist, MGH; and David Peal, Ph.D., Assistant in Biology, MGH), and developmental biology with mouse modeling (Russell Norris, Ph.D.,Assistant Professor in the Department of Regenerative Medicine and Cell Biology at the Medical University of South Carolina), with funding provided the by the Leducq Foundation Transatlantic Network of Excellence for Mitral Valve Disease, helping to provide confirmatory evidence (Xavier Jeunemaitre, Ph.D., Professor of Genetics, University of Paris, France; and Jean-Jacques Schott, Ph.D.,Inserm Senior Researcher in Cardiovascular Genetics, Inserm UMR915, Nantes, France. In a meeting with the press, the researchers noted that a number of connective tissue disorders, such as Marfan syndrome, also frequently feature MVP as one of their constellation of symptoms. In Marfan syndrome, MVP occurs in 50% of patients. Interestingly, the researchers noted that there is also a possible connection with polycystic kidney disease (PKD). They noted that the DCHS1 knockout mice actually develop polycystic kidneys. In discussing the possible function of the DCHS1 gene, the researchers noted that it seems to be involved in the polarization of cells, allowing them to know where they are and how they are oriented relative to other cells, and to ultimately become aligned, during development, in the proper orientation. Although there are other valves in the heart, only the mitral valve is affected by mutations of DCHS1. The reason for this is unknown, but the scientists suggested it might be related to the strong forces that are exerted on the mitral valve relative to those exerted on the other valves. This BioQuick report is based largely on an ASHG press release. The ASHG is the primary professional membership organization for nearly 8,000 human genetics specialists worldwide. The ASHG Annual Meeting is the world's largest gathering of human genetics professionals and a forum for renowned experts in the field. Approximately 6,700 genetics professionals are attending the 2013 annual meeting in Boston, which runs through Saturday, October 26. For more information about the ASHG, visit: [ASHG press release] [ASHG Annual Meeting 2013]