Genetic Predisposition To Thoracic Aortic Aneurysms/Dissections

胸主动脉瘤/夹层的遗传倾向

基本信息

批准号：
8828767
负责人：
DIANNA M MILEWICZ
金额：
$ 59.31万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-12 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828767
关键词：
Accounting Actins Acute Affect Age of Onset Aneurysm Aortic Diseases Bioinformatics Blood Vessels Candidate Disease Gene Cause of Death Cessation of life Chest Chromosome Mapping Clinical Clinical Management Congenital Abnormality Data Data Linkages Disease Disease Management Dissection Etiology FBN1 Family Family history of Gene Family Gene Mutation Gene Proteins Genes Genetic Genetic Heterogeneity Genetic Predisposition to Disease Genome Goals Growth Factor Receptors Heterogeneity Individual Inherited Intracranial Aneurysm Lead Location MADH3 gene MYH11 gene MYLK gene Maps Medical Molecular Molecular and Cellular Biology Morbidity - disease rate Muscle Contraction Mutate Mutation Mutation Spectra Myosin ATPase Myosin Light Chain Kinase Operative Surgical Procedures Pathogenesis Pathologic Pathology Patients Penetrance Phenotype Phosphotransferases Prevention Protein Isoforms Proteins Recommendation Recruitment Activity Relative (related person)Research Research Personnel Risk Role Sampling Signal Transduction Smooth Muscle Smooth Muscle Myocytes Syndrome TGFBR1 gene TGFBR2 gene Thoracic Aortic Aneurysm Thoracic aorta Time Transforming Growth Factors Translating United States Vascular Diseases base bicuspid aortic valve clinical care clinical phenotype cohort exome sequencing family management gene discovery genetic pedigree genome sequencing improved insight member mortality mutation carrier novel positional cloning premature prevent proband protein function rare variant repaired

项目摘要

DESCRIPTION (provided by applicant): Thoracic aortic aneurysms and dissections are the major diseases affecting the thoracic aorta and a common cause of morbidity and mortality in the United States. Thoracic aortic aneurysms progressively enlarge over time and ultimately lead to acute aortic dissections (TAAD); if the aneurysm is surgically repaired prior to dissection premature deaths can be prevented. TAAD is inherited in an autosomal dominant manner with variable expression and decreased penetrance in up to 20% of TAAD patients (Familial TAAD). We have mapped five chromosomal loci for FTAAD and identified five genes that when mutated cause FTAAD, FBN1, TGFBR2, TGFBR1, ACTA2, and MYLK; other investigators have identified MYH11 as a sixth gene. Recently, family-based exome sequencing identified mutations in SMAD3 as the seventh gene causing FTAAD. In total, mutations in these genes are responsible for approximately 20% of FTAAD. Identification of these genes has provided insight into the pathogenesis of the disease, highlighting aberrant transforming growth factor-¿ signaling and disrupted smooth muscle contraction as factors contributing to TAAD. Correlation between mutations in specific genes and the corresponding phenotype has revealed unique features associated with each gene, leading to recommendation that disease management in FTAAD families be based on the specific genetic defect. We hypothesize that there are multiple genes responsible for familial TAAD, and this genetic heterogeneity underlies the significant clinical heterogeneity observed in FTAAD. The long term goal of the project is to identify the genes that cause FTAAD and characterize the associated phenotype. The first aim is to recruit families with two or more members with TAAD, collect samples, and characterize the clinical phenotype of these families. The second aim is to map chromosomal loci for FTAAD using large families with multiple affected members. The third aim is to identify novel FTAAD genes through exome sequencing of affected relative pairs from large families and combining these data with the linkage data to efficiently identify rare variants in disease-causing genes. Finally, initial pathologic, cellular, and molecular studies will be done to begin to understand the effect of gene mutations on aortic function. Through these studies, we will improve understanding of the etiology of aortic diseases and provide data critical for the proper clinical management of familia thoracic aortic disease.

描述（由适用提供）：胸腔主动脉瘤和解剖是影响胸主动脉的主要疾病，是美国发病率和死亡率的常见原因。随着时间的流逝，胸动脉瘤逐渐变大，最终导致急性主动脉夹层（TAAD）；如果在解剖过早死亡之前对动脉瘤进行手术修复。 TAAD以常染色体显性方式遗传，表达可变，高达20％的TAAD患者（家族性TAAD）提高了渗透率。我们已经为FTAAD绘制了五个染色体基因座，并确定了五个基因，当突变引起FTAAD时，FBN1，TGFBR2，TGFBR1，ACTA2和MYLK；其他研究人员将MYH11确定为第六基因。最近，基于家庭的外显子组测序将SMAD3中的突变鉴定为引起FTAAD的第七基因。这些基因的突变总数约占FTAAD的20％。这些基因的鉴定已提供了对疾病发病机理的见解，突出了异常转化生长因子 - 信号传导和平滑肌肉收缩的破坏，这是导致TAAD的因素。特定基因中的突变与相应的表型之间的相关性揭示了与每个基因相关的独特特征，从而建议FTAAD家族中的疾病管理基于特定的遗传缺陷。我们假设有多个基因负责农场TAAD，而这种遗传异质性是FTAAD中观察到的显着临床异质性的基础。该项目的长期目标是确定引起FTAAD的基因并表征相关的表型。第一个目的是招募有两个或更多成员的TAAD，收集样本的家庭，并表征这些家庭的临床表型。第二个目的是使用具有多个受影响成员的大家庭绘制FTAAD的染色体位置。第三个目的是通过对大型家族的影响相对对的外显子组测序来鉴定新的FTAAD基因，并将这些数据与链接数据结合在一起，以有效地识别引起疾病的基因中的罕见变异。最后，将进行初始病理，细胞和分子研究，以开始了解基因突变对主动脉功能的影响。通过这些研究，我们将提高对主动脉疾病病因的理解，并为对主动脉疾病的适当临床管理提供至关重要的数据。