Identification of a Gene Causing Aortic Stenosis

导致主动脉瓣狭窄的基因的鉴定

• 批准号: 6855925
• 负责人: PETER N BOWERS
• 金额: $ 24.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6855925
• 关键词: aortic valve stenosis; autosomal dominant trait; chromosome aberrations; clinical research; echocardiography; family genetics; gene dosage; gene mutation; genetic screening; human genetic material tag; human subject; linkage mapping; pathologic process; patient oriented research

DESCRIPTION (provided by applicant): This proposal seeks to identify a gene causing aortic stenosis (AS), a complex human genetic trait with substantial burden on our nations' cardiovascular health. Epidemiologic studies with high familial recurrence rates and chromosomal anomalies strongly implicate a genetic cause, yet to date, no genes have been identified to cause AS in human. Our approach to disease gene identification is to recruit genetically informative families demonstrating rare Mendelian inheritance to perform linkage analysis and identify the disease gene in the linked interval. This postional cloning approach has been a highly successfully means of disease gene identification, especially in complex traits. Towards this end, we have recruited a four-generation family with 13 members affected with AS that demonstrates autosomal dominant inheritance. Echocardiography confirmed the phenotype assignment in all affected family members. Multipoint linkage analysis using in a 10cM genome wide scan has identified a single 1Mb AS locus that achieves the predicted maximum LOD score of 3.0. All affected individuals are linked and 3 unaffected individuals are linked demonstrating incomplete penetrance. By using a positional cloning approach in this pedigree, we have identified a single AS locus in human. Identification of the AS gene contained in this 1Mb disease-linked interval is the overall purpose in the 3 Specific Aims we propose to 1. Characterize and identify candidate genes in the AS interval, 2. Mutation screen candidate genes in the AS interval; and 3. Evaluate for a gene dose effect in the AS interval. With identification of the AS gene, we will evaluate its overall contribution to the pathogenesis of AS and related disorders and will begin the characterization and functional assessment of this gene during cardiac development. Our linkage result holds the promise of identifying the first gene to cause AS in human and provides the opportunity for novel insights into the disease pathogenesis of this common complex human trait.

描述（由申请人提供）：该提案旨在识别引起主动脉狭窄的基因（AS），这是一种复杂的人类遗传特征，对我们国家的心血管健康负担很大。具有较高家族性复发率和染色体异常的流行病学研究强烈暗示了遗传原因，但迄今为止，尚未发现基因像人类那样引起。我们的疾病基因鉴定方法是招募遗传信息丰富的家庭，表现出罕见的孟德尔遗传来进行连锁分析，并在链接的间隔中识别疾病基因。这种邮政克隆方法一直是一种高度成功的疾病基因鉴定手段，尤其是在复杂的特征中。为此，我们已经招募了一个四代家庭，其中有13名成员受到影响，因为这表明了常染色体主导的遗传。超声心动图证实了所有受影响家庭成员的表型分配。使用10厘米基因组宽扫描中的多点链接分析已将单个1MB识别为实现预测的最大LOD得分为3.0的基因座。所有受影响的个体都是链接的，有3个未受影响的个体链接出来，表现出不完整的渗透率。通过在该血统中使用位置克隆方法，我们已经确定了人类中的单个位置。在这个1MB疾病连接的间隔中识别AS基因是我们建议1的3个特定目标中的总体目的。在AS间隔中表征和鉴定候选基因，2。突变筛选候选基因在AS间隔中；和3。在AS间隔中评估基因剂量效应。通过鉴定AS基因，我们将评估其对AS和相关疾病发病机理的总体贡献，并将开始对心脏发育期间该基因的表征和功能评估。我们的联系结果有望确定第一个基因引起的人类，并为对这种常见的复杂人类性状的疾病发病机理提供了新的机会。