FAMILIAL AORTIC ANEURYSM: A MOLECULAR GENETIC ANALYSIS

描述(申请人逐字描述)：主动脉瘤是一种常见的 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 它们破裂会造成毁灭性的临床后果。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 常染色体显性遗传性家族性主动脉瘤(FAA)可发生为 Marfan和Ehler-Danlos IV型综合征，大多数FAA患者没有 符合这些结缔组织疾病的诊断标准，并且 长期以来，人们一直假设存在无关的FAA基因和突变。至 然而，到目前为止，还没有发现其他基因缺陷。在这个项目中，我们 将确定FAA基因(S)对主动脉瘤的形成负责。我们有 使用超声心动图技术识别7个受艾滋病影响的家庭 无心外血管临床表现的常染色体显性遗传性FAA 结缔组织病。家系ANB的连锁分析表明，FAA，in 这个家系是由纤维蛋白-1基因座缺陷引起的，是一个 纤维素病。然而，连锁分析表明，联邦航空局在另一个 亲缘关系(ANA)与纤维蛋白-1、纤维蛋白-2或III型无关 前胶原基因。因此，ANA家族中的主动脉瘤并不代表 形成马凡或埃勒斯-丹洛斯综合征。亲属大小，常染色体 显性遗传和高外显度使FAA在ANA和ANA中 其他已鉴定的特别适合分子遗传分析的家系。 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ANA的程度 确定突变基因位置的FAA遗传异质性(S) 在其他家族中进行分离，(3)完善每个家族的遗传和物理图谱 FAA基因座和识别候选基因，(4)识别突变基因 这会导致FAA，以及(5)评估FAA基因在导致 非家族性主动脉瘤。全基因组连锁分析目前 正在确定与FAA有关的基因的染色体位置 在全日空家庭和其他家庭。一旦确定FAA基因座，我们将研究 确定联邦航空局相对贡献率的几个大大小小的家庭 这些人群中主动脉瘤形成的基因座。然后，我们将雇用 定位克隆技术鉴定FAA特异性基因缺陷(S) 染色体基因座。慢性阻塞性肺疾病患者这些基因的突变分析 散发性主动脉瘤将决定它们在 常见的非家族性主动脉瘤。我们预计，确认 与血管壁不稳定和动脉瘤有关的新基因 队形将增强我们对个体进行临床前诊断的能力 处于危险之中。此外，对这些基因的表征将为 心血管疾病实验模型的建立与发展 预防或延缓主动脉瘤的创新药物策略 队形。

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.