Genetics and Mechanisms of Mitral Valve Prolapse

二尖瓣脱垂的遗传学和机制

• 批准号: 9258482
• 负责人: David J Milan
• 金额: $ 75.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258482
• 关键词: Adult; Affect; Affinity; American; Binding Proteins; Calcineurin; Candidate Disease Gene; Cardiac Surgery procedures; Cell Polarity; Cell Proliferation; Childhood; Chromosomes; Clinical Treatment; Congestive Heart Failure; Cysteine-Rich Domain; DNA; Data; Data Set; Defect; Development; Diagnostic; Disease; Drosophila genus; Embryo; Endocarditis; FBN1; Functional disorder; Funding; General Hospitals; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Goals; Growth; Half-Life; Heart Diseases; Heart Valves; Heritability; Human; Impairment; In Vitro; Integrins; Investigation; Knockout Mice; Laboratories; Lead; Length; Link; Marfan Syndrome; Massachusetts; Medical; Medicine; Microfilaments; Mitral Valve; Mitral Valve Insufficiency; Mitral Valve Prolapse; Modeling; Molecular Abnormality; Morbidity - disease rate; Mus; Mutation; Neurology; Onset of illness; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Phenotype; Play; Population; Prevention; Proteins; Proteomics; Ptosis; Publishing; Research Personnel; Risk; Role; Seminal; Shapes; Signal Transduction; South Carolina; Stem cells; Thick; Universities; Work; Zebrafish; case control; cell growth; cell motility; cohort; common treatment; drug discovery; filamin; genetic variant; genome wide association study; genome-wide; knock-down; mortality; mouse model; mutant; new therapeutic target; novel; prevent; professor; public health relevance; tensin

 DESCRIPTION (provided by applicant): Mitral valve prolapse (MVP) affects 2.4% of the population and results in more than 7,000 open heart surgeries each year in the US alone. MVP is characterized by excessive valve leaflet growth resulting in prolapse, impaired valve closure and mitral regurgitation (MR), which can cause serious complications including endocarditis and congestive heart failure. Fibrillin-1 mutations cause MVP in Marfan syndrome and Filamin A mutations cause an X-linked form of pan-valvular myxomatous dystrophy, but to date, despite a clear heritable component, no genes have been identified for non-syndromic MVP. However, we now have compelling, soon to be published data from two approaches that significantly advance our understanding of the genetics of MVP. First, we have identified mutations in Dachsous 1 (DCHS1) as a cause of MVP. DCHS1 was discovered in Drosophila and plays an important role in cell growth and polarity. Knockdown of zebrafish dchs1 resulted in atrioventricular regurgitation that could not be rescued by the mutant human protein. In vitro studies of mutant and wild type forms of human DCHS1 revealed reduced half-life of the mutant protein. Finally the haploinsufficient Dchs1 mouse displays classic MVP with altered leaflet length and thickness and functional prolapse. These results confirm a role for DCHS1 in mitral valve disease. Second, we recently completed a genome wide association study (GWAS) to identify common genetic variants associated with MVP. Using a population of 2,854 cases we identified 6 novel genetic loci that reached genome wide significance and replicated in independent cohorts. In order to identify causal genes we knocked down candidate genes from three loci in zebrafish, identifying two genes that cause a valve phenotype: Tensin 1, (TNS1) an integrin and actin filament binding protein, and LIM and cysteine-rich domains 1 (LMCD1), which augments calcineurin/NFAT signaling. These genes are excellent functional candidates for MVP. Our exciting preliminary data set the stage for mechanistic investigation into the pathogenesis of MVP. Our hypothesis is that the newly identified genes regulate cell migration during development which, when perturbed, results in MVP. Specifically, we aim to: 1.Expand the network of MVP genes by: a. evaluating the remaining GWAS loci, b. performing comprehensive protein interaction studies using affinity proteomics, and c. explore the role of the MVP gene network in regulating cellular migration, 2. Investigate the mechanism of valve dysfunction in Tns1 knockout mice, and 3. Determine the burden of mutations in MVP genes by performing DNA capture and sequencing in a large case-control cohort. Mitral valve prolapse is a cause of significant morbidity and mortality. There are currently no treatments short of surgery, in part because the pathogenesis is poorly understood. Given these challenges, we believe that our work on the newly discovered MVP genes will facilitate a greater understanding of MVP and may ultimately provide novel targets for prevention and treatment of this common and clinically important disease.