MUTANT ANALYSIS OF TSC1 & TSC2 IN TSC RELATED DISORDERS

TSC1 突变分析

• 批准号: 6522605
• 负责人: SANDRA L DABORA
• 金额: $ 30.67万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-26 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6522605
• 关键词: autosomal dominant trait; clinical research; diagnosis design /evaluation; family genetics; gene deletion mutation; genetic disorder diagnosis; genetic screening; high performance liquid chromatography; high throughput technology; human subject; mental disorder diagnosis; nervous system disorder diagnosis; tuberous sclerosis

The goals of this proposal are to develop robust, sensitive, and high throughput methods for mutation analysis for the tumor suppressor syndrome, tuberous sclerosis complex (TSC). These methods will be immediately useful for clinical purposes but will also be valuable research tools for analysing the molecular pathology in TSC and related disorders. The technology developed during this project will be directly applicable to the study of genetic variation in other disorders as well. TSC is a familial tumor syndrome characterized by the development of benign tumors (hamartomas) in multiple organs. Although it is inherited in an autosomal dominant pattern, the majority of new cases (about 65 percent) are sporadic without antecedent family history. Penetrance is high but expression is variable with both severely and mildly affected individuals. Organs most frequently involved are the brain, skin, kidneys and heart. Neurologic morbidity from seizures, mental retardation and behavior disorders is common. Two disease genes, TSC1 and TSC2 have been identified recently. Unfortunately the development of a genetic test has been hindered by the large size of the two genes and the diversity of the mutation spectrum in TSC. The R21 portion of this grant focuses on the development and optimization of a series of 3 assays which will allow for high throughput comprehensive genetic analysis for TSC. The R33 portion of this proposal focuses on using comprehensive mutation analysis for TSC to collect genotype and clinical data on a large cohort of TSC patients. Comprehensive mutation detection methods will also be used to study the role of TSC1 and TSC2 in related disorders as well as in TSC lesions and related non-TSC tumors. There is currently much demand from TSC patients and families for comprehensive mutation analysis for family planning and prenatal diagnosis, diagnosis confirmation, and prognostic information. The proposed plan of study will address this issue as well as help elucidate the role of TSC1 and TSC2 in the molecular pathology of TSC lesions and non-TSC tumors.

该提案的目标是开发稳健、灵敏且高通量的方法，用于肿瘤抑制综合征、结节性硬化症 (TSC) 的突变分析。 这些方法将立即用于临床目的，但也将成为分析 TSC 和相关疾病的分子病理学的有价值的研究工具。 该项目期间开发的技术也将直接适用于其他疾病的遗传变异研究。 TSC 是一种家族性肿瘤综合征，其特征是多个器官出现良性肿瘤（错构瘤）。 尽管它以常染色体显性遗传模式遗传，但大多数新病例（约 65%）是散发性的，没有既往家族史。 外显率很高，但表达在严重和轻度受影响的个体中存在差异。 最常涉及的器官是大脑、皮肤、肾脏和心脏。 癫痫发作、智力低下和行为障碍引起的神经系统发病很常见。 最近已鉴定出两种疾病基因 TSC1 和 TSC2。 不幸的是，基因测试的发展因 TSC 中两个基因的大尺寸和突变谱的多样性而受到阻碍。该资助的 R21 部分重点关注一系列 3 种检测的开发和优化，这将允许对 TSC 进行高通量综合遗传分析。 该提案的 R33 部分重点是使用 TSC 的综合突变分析来收集大量 TSC 患者的基因型和临床数据。 综合突变检测方法还将用于研究 TSC1 和 TSC2 在相关疾病以及 TSC 病变和相关非 TSC 肿瘤中的作用。目前，TSC患者和家庭对全面的突变分析有很大的需求，以用于计划生育和产前诊断、诊断确认和预后信息。拟议的研究计划将解决这个问题，并帮助阐明 TSC1 和 TSC2 在 TSC 病变和非 TSC 肿瘤的分子病理学中的作用。