FAMILIAL AORTIC ANEURYSM: A MOLECULAR GENETIC ANALYSIS

家族性主动脉瘤：分子遗传学分析

• 批准号: 6645673
• 负责人: CRAIG T BASSON
• 金额: $ 47.61万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6645673
• 关键词: aorta aneurysm; autosomal dominant trait; biotechnology; congenital cardiovascular disorder; echocardiography; family genetics; gene mutation; human genetic material tag; human subject; linkage mapping; molecular genetics; patient oriented research

DESCRIPTION (the applicant's description verbatim): Aortic aneurysm is an often fatal cardiovascular disease. Many aortic aneurysms are clinically silent until they rupture with devastating clinical consequences. At least 20 percent of aortic aneurysms result from hereditary mendelian disorders. Although monogenic autosomal dominant familial aortic aneurysm (FAA) can occur as one feature of Marfan and Ehlers-Danlos Type IV syndromes, most individuals with FAA do not satisfy diagnostic criteria for these connective tissue disorders, and the existence of unrelated FAA genes and mutations has long been hypothesized. To date, however, no other gene defect has been identified. In this project, we will identify FAA gene(s) responsible for aortic aneurysm formation. We have used echocardiographic techniques to identify 7 families who are affected by autosomal dominant FAA without clinical findings of extracardiovascular connective tissue disease. Linkage analysis of family ANB reveals that FAA, in this kindred, results from a fibrillin-1 gene locus defect and is a fibrillinopathy. However, linkage analysis demonstrates that FAA in another kindred (ANA) is not linked to the fibrillin-1, fibrillin-2, or the type III procollagen genes. Therefore, aortic aneurysms in family ANA do not represent a forme fruste of Marfan or Ehlers-Danlos syndromes. Kindred size, autosomal dominant inheritance, and the high degree of penetrance make FAA in ANA and other identified families particularly suitable for molecular genetic analysis. We therefore propose: (1) To identify the chromosomal location of the gene responsible for monogenic FAA in family ANA, (2) To characterize the extent of FAA genetic heterogeneity by defining the location of the mutated gene(s) segregating in other families, (3) To refine genetic and physical maps of each FAA locus and identify candidate genes, (4) To identify genes with mutations that cause FAA, and (5) To assess the role of the FAA gene in causing nonfamilial aortic aneurysms. Genome wide linkage analysis is currently underway to establish the chromosomal location of the genes responsible for FAA in family ANA and other families. Once FAA loci are identified, we will study several large and small families to determine the relative contributions of FAA loci to aortic aneurysm formation in these populations. We will then employ positional cloning technology to identify the specific gene defect(s) at FAA chromosomal loci. Mutational analysis of these genes in individuals with sporadic aortic aneurysms will define their contribution to the genesis of common nonfamilial aortic aneurysms. We anticipate that the identification of novel genes which contribute to vascular wall instability and aneurysm formation will enhance our ability to make preclinical diagnoses in individuals at risk. Moreover, characterization of these genes will provide a platform for the development of experimental models of cardiovascular disease and to develop innovative pharmacologic strategies to prevent or to retard aortic aneurysm formation.

描述（申请人的描述逐字描述）：主动脉动脉瘤通常是 致命的心血管疾病。许多主动脉瘤在临床上保持沉默直到 它们破裂，临床后果破坏。至少20％ 主动脉瘤是由遗传性孟德尔疾病引起的。虽然是单基因的 常染色体显性家族主动脉瘤（FAA）可以作为一项特征。 Marfan和Ehlers-Danlos IV综合征，大多数FAA的人都不 满足这些结缔组织障碍的诊断标准， 长期以来已经假设存在无关的FAA基因和突变。到 但是，尚未确定其他基因缺陷。在这个项目中，我们 将确定负责主动脉动脉瘤形成的FAA基因。我们有 使用超声心动图技术来识别7个受影响的家庭 常染色体显性FAA，没有临床发现 结缔组织疾病。家庭ANB的连锁分析表明，FAA， 这种亲属来自原纤维蛋白-1基因座基因座缺陷，是一个 纤维蛋白原病。但是，链接分析表明另一个FAA 亲属（ANA）与Fibrillin-1，Fibrillin-2或III型没有链接 Procollagen基因。因此，家庭中主动脉瘤不代表 Marfan或Ehlers-Danlos综合征的Forme Fruste。同类尺寸，常染色体 占主导地位，高度的外观使FAA在ANA和 其他鉴定出的家庭特别适合分子遗传分析。 因此，我们建议：（1）识别基因的染色体位置 负责家庭ANA中的单基因FAA，（2）以表征 FAA遗传异质性通过定义突变基因的位置 在其他家庭中隔离，（3）以完善每个家庭的遗传和物理图 FAA基因座并识别候选基因，（4）以识别具有突变的基因 这会导致FAA，（5）评估FAA基因在引起的作用 非家族主动脉瘤。基因组广泛的链接分析目前正在 正在建立负责FAA基因的染色体位置 在家庭和其他家庭中。一旦确定了FAA基因座，我们将学习 几个大小家庭来确定FAA的相对贡献 这些人群中主动脉动脉瘤形成的基因座。然后我们将雇用 位置克隆技术以识别FAA的特定基因缺陷 染色体基因座。这些基因的突变分析 零星主动脉瘤将定义其对起源的贡献 常见的非家庭主动脉瘤。我们预计会识别 新的基因有助于血管壁不稳定性和动脉瘤 形成将增强我们在个人中做出临床前诊断的能力 有风险。此外，这些基因的表征将为 开发心血管疾病的实验模型并发展 预防或阻碍主动脉瘤的创新药理学策略 形成。