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.

 描述（由适用提供）：二尖瓣脱垂（MVP）影响2.4％的人口，仅在美国，每年就会进行7,000多次开放心脏手术。 MVP的特征是瓣膜叶片生长过多，导致脱垂，瓣膜闭合和二尖瓣反流（MR），这可能会导致严重的并发症，包括心内膜炎和充血性心力衰竭。纤维蛋白-1突变导致MARFAN综合征中的MVP和Filamin A突变引起X连锁形式的泛缺腹性毛状腺肿性营养不良，但迄今为止，希望有明显的可遗传分量，尚未确定基因对于非含量MVP。但是，我们现在具有引人注目的是，很快就会从两种方法中发表数据，这些方法可以大大推动我们对MVP遗传学的理解。首先，我们已经将二豆1（DCHS1）中的突变确定为MVP的原因。 DCHS1在果蝇中发现，在细胞生长和极性中起重要作用。杀伤斑马鱼DCHS1导致房屋反流，而突变的人类蛋白无法营救。对突变体和野生型人类DCHS1的体外研究表明，突变蛋白的半衰期减少了。最后，单倍助理的DCHS1小鼠显示了经典的MVP，其小叶长度和厚度和功能脱垂。这些结果证实了DCHS1在二尖瓣疾病中的作用。其次，我们最近完成了一项基因组广泛的关联研究（GWAS），以识别与MVP相关的常见遗传变异。使用2,854例病例的人群，我们确定了6个新的遗传基因座，这些基因群具有广泛的意义并在独立的同类群中复制。为了鉴定因果基因，我们从斑马鱼中的三个基因座中击倒了候选基因，确定了两个引起瓣膜表型的基因：tensin 1，（TNS1）整合素和肌动蛋白丝结合蛋白，LIM和富含CySteine的富含CySteine-rich roch域1（LMCD1），这增强了钙氨酸/nfatsinecinerin/nfatsinfat signalliin/nfats Signallations Signallian/nfats Signallats Signalling。这些基因是MVP的出色功能候选。我们令人兴奋的初步数据为机械投资奠定了MVP发病机理的阶段。我们的假设是，新近鉴定的基因在发育过程中调节细胞迁移，而在受到干扰后会导致MVP。具体而言，我们的目标是：1。扩展MVP基因网络：评估其余的GWAS位点，b。使用亲和力蛋白质组学进行全面的蛋白质相互作用研究，c。探索MVP基因网络在调节细胞迁移中的作用，2。研究TNS1敲除小鼠瓣膜功能障碍的机制，3。通过在大病例对照组中执行DNA捕获和测序来确定MVP基因中突变的燃烧。二尖瓣脱垂是发病率明显的原因。目前尚无手术治疗，部分原因是发病机理知之甚少。鉴于这些挑战，我们认为我们在新发现的MVP基因上的工作将有助于对MVP有更多了解，并最终可能为预防和治疗这种常见和临床重要疾病提供新的目标。