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（申请人的逐字描述）：主动脉瘤是一种常见的疾病。 致命的心血管疾病。许多主动脉瘤在临床上是无症状的，直到 它们破裂会带来毁灭性的临床后果。至少 20% 主动脉瘤由遗传性孟德尔疾病引起。虽然单基因 常染色体显性家族性主动脉瘤（FAA）可能是以下特征之一： 马凡 (Marfan) 和埃勒斯-当洛斯 (Ehlers-Danlos) IV 型综合征，大多数患有 FAA 的人没有 满足这些结缔组织疾病的诊断标准，并且 长期以来人们一直假设存在不相关的 FAA 基因和突变。到 然而，迄今为止尚未发现其他基因缺陷。在这个项目中，我们 将识别负责主动脉瘤形成的 FAA 基因。我们有 使用超声心动图技术确定了 7 个受此影响的家庭 常染色体显性 FAA，无心血管外临床表现 结缔组织疾病。家族 ANB 的连锁分析表明，FAA 在 这个家族是由 fibrillin-1 基因位点缺陷引起的，是 纤维蛋白病。然而，关联分析表明，FAA 在另一个 kindred (ANA) 与 fibrillin-1、fibrillin-2 或 III 型无关 前胶原蛋白基因。因此，ANA家族中的主动脉瘤并不代表 形成马凡综合征或埃勒斯-当洛斯综合征。近亲大小，常染色体 显性遗传和高外显率使 FAA 成为 ANA 和 其他已确定的特别适合分子遗传分析的家族。 因此我们建议：（1）确定该基因的染色体位置 负责 ANA 家族中的单基因 FAA，(2) 表征 FAA 通过定义突变基因的位置来确定遗传异质性 在其他科中分离，（3）完善每个科的遗传和物理图谱 FAA 基因座并鉴定候选基因，(4) 鉴定具有突变的基因 (5) 评估 FAA 基因在引起 FAA 中的作用 非家族性主动脉瘤。目前全基因组连锁分析 正在进行中以确定负责 FAA 的基因的染色体位置 在全日空家庭和其他家庭。一旦确定了 FAA 位点，我们将研究 几个大小家庭来确定 FAA 的相对贡献 这些人群中主动脉瘤形成的位点。然后我们将雇用 FAA 使用定位克隆技术识别特定基因缺陷 染色体位点。对患有此类疾病的个体进行这些基因的突变分析 散发性主动脉瘤将定义其对以下疾病发生的贡献： 常见的非家族性主动脉瘤。我们预计，鉴定 导致血管壁不稳定和动脉瘤的新基因 形成将增强我们对个人进行临床前诊断的能力 有危险。此外，这些基因的表征将为 心血管疾病实验模型的开发和开发 预防或延缓主动脉瘤的创新药理学策略 形成。