GENETICS CORE

遗传学核心

• 批准号: 6870602
• 负责人: VIVIANNA M VAN DEERLIN
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870602
• 关键词: aging; biomedical facility; cerebral degeneration; gene mutation; genetic counseling; genetic screening

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized clinically by changes in personality, social behavior, executive function, and/or language dysfunction, often in association with a movement disorder. The clinical manifestations of FTD are correlated with degeneration of the frontal and anterior temporal lobes. FTD can present either sporadically or as a familial disorder. Some of these kindred demonstrate an autosomal dominant pattem of inheritance. Elucidation of linkage to chromosome 17 and the subsequent identification of mutations in the tau gene (MAPT) in FTD cases provided direct evidence that tau protein dysfunction can lead to neurodegeneration. More than 30 different MAPT mutations have been identified. Studying familial forms of FTD can help elucidate the etiology and pathophysiology of FTD. Since FTDs are clinically heterogeneous, it is imperative to collect and study a large number of kindred to identify new mutations in MAPT and discover novel disease-associated genes. We began to collect DNA samples from individuals and families with FTD or related neurodegenerative disorders with the goal of enabling research genetic studies of such conditions. We now propose the formal establishment of a Genetics Core as a part of the Program Project Grant (PPG), Frontotemporal Dementias: Genotypes and Phenotypes to continue and expand this effort. The Genetics Core will provide genetic counseling to individuals and families with FTD and support the on-going collection and storage of DNA from these families. Limited genetic analysis of known genes associated with FTD will be performed to identify mutations. Finally clinically-relevant genetic tests will be translated to the clinical (CLIA-approved) laboratory. The collection of well-defined FTD cohorts and/or identification of new mutations will support genetic discoveries from Project 2, help advance the clinical characterization of FTD in Project 1, enable detailed biochemical and immunohistochemical analyses of FTD (Project 3), lead to the generation of new animal models of disease (Projects 2 & 4), and serve as a resource for genetic analysis of pathologically diagnosed cases of FTD in the Neuropathology Core to facilitate correlations between genotype and the clinical, neuropathological, and biochemical phenotypes.

额颞叶痴呆（FTD）是一种神经退行性疾病，临床特征为人格、社会行为、执行功能和/或语言功能障碍的变化，通常与运动障碍相关。FTD的临床表现与额叶和前颞叶的变性相关。FTD可作为散发性疾病或家族性疾病出现。这些亲属中的一些表现出常染色体显性遗传模式。在FTD病例中阐明了与17号染色体的连锁关系，并随后鉴定了tau基因（MAPT）突变，这提供了tau蛋白功能障碍可导致神经退行性变的直接证据。已经鉴定了30多种不同的MAPT突变。研究家族性FTD有助于阐明FTD的病因和病理生理学。由于FTDs在临床上是异质性的，因此必须收集和研究大量的亲属以鉴定MAPT中的新突变并发现新的疾病相关基因。 我们开始从FTD或相关神经退行性疾病的个人和家庭中收集DNA样本，目的是对这些疾病进行遗传学研究。我们现在提议正式建立遗传学核心，作为额颞叶痴呆症：基因型和表型计划项目资助（PPG）的一部分，以继续和扩大这一努力。遗传学核心将为患有FTD的个人和家庭提供遗传咨询，并支持从这些家庭持续收集和储存DNA。将对FTD相关的已知基因进行有限的遗传分析，以确定突变。最后，临床相关的基因检测将被转移到临床（CLIA批准的）实验室。收集明确定义的FTD队列和/或鉴定新突变将支持项目2的遗传发现，有助于推进项目1中FTD的临床表征，实现FTD的详细生化和免疫组织化学分析（项目3），导致新的疾病动物模型的产生（项目2和4），并作为神经病理学核心中FTD病理诊断病例的遗传分析资源，以促进基因型与临床、神经病理学和生化表型之间的相关性。