FAMILIAL AORTIC ANEURYSM: A MOLECULAR GENETIC ANALYSIS

描述（申请人的逐字描述）：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没有症状， 它们会破裂并带来毁灭性的临床后果。至少20%的 主动脉瘤由遗传性孟德尔紊乱引起。虽然单基因 常染色体显性遗传家族性主动脉瘤（FAA）可作为 Marfan和Ehlers-Danlos IV型综合征，大多数患有FAA的个体没有 符合这些结缔组织疾病的诊断标准， 长期以来一直假设存在不相关的FAA基因和突变。到 然而，迄今为止，没有发现其他基因缺陷。本课题 将确定负责主动脉瘤形成的FAA基因。我们有 使用超声心动图技术，以确定7个家庭谁是受影响的 无心外血管临床表现的常染色体显性FAA 结缔组织病家族ANB的连锁分析表明，FAA，在 这种家族是由一个casein-1基因位点缺陷引起的， 纤维蛋白病然而，连锁分析表明，FAA在另一个 亲属（ANA）不与抗肿瘤蛋白-1、抗肿瘤蛋白-2或III型相关， 前胶原基因。因此，ANA家族的主动脉瘤并不代表 或Ehlers-Danlos综合征。亲属大小，常染色体 显性遗传和高度的遗传多态性使ANA和 其他特别适合于分子遗传分析的已鉴定的家族。 因此，我们建议：（1）确定该基因的染色体定位 ANA家族中单基因型FAA的发生，（2）为了表征ANA家族中单基因型FAA的程度， 通过定义突变基因的位置确定FAA遗传异质性 在其它家系中分离，（3）细化每个家系的遗传图谱和物理图谱 FAA位点，并确定候选基因;（4）确定突变基因 （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 目前正在建立FAA基因的染色体定位， ANA家庭和其他家庭。一旦FAA基因位点被确定，我们将研究 几个大小家庭，以确定联邦航空局的相对贡献 在这些人群中与主动脉瘤形成相关的基因位点。然后我们将雇用 定位克隆技术用于识别FAA的特定基因缺陷 染色体位点这些基因的突变分析在个人与 散发性主动脉瘤将确定其对 常见的非家族性主动脉瘤我们预计， 导致血管壁不稳定和动脉瘤的新基因 形成将提高我们的能力，使临床前诊断的个人 处于危险之中此外，对这些基因的表征将提供一个平台， 心血管疾病实验模型的开发， 预防或延缓主动脉瘤创新药物策略 阵

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.