GENETICS CORE

额颞叶痴呆(FTD)是一种神经退行性疾病，临床表现为个性、社会行为、执行功能和/或语言障碍的改变，通常与运动障碍有关。FTD的临床表现与额叶和前颞叶的退变有关。FTD既可以表现为散发性，也可以表现为家族性疾病。其中一些家系表现出常染色体显性遗传模式。与17号染色体连锁的阐明和随后在FTD病例中发现的tau基因(MAPT)突变为tau蛋白功能障碍可导致神经变性提供了直接证据。目前已鉴定出30多种不同的MAPT突变。研究FTD的家族性形式有助于阐明FTD的病因和病理生理学。由于FTD在临床上具有异质性，因此有必要收集和研究大量的家系，以确定MAPT的新突变，并发现新的疾病相关基因。 我们开始收集患有FTD或相关神经退行性疾病的个人和家庭的DNA样本，目的是使对这些疾病的研究成为可能。我们现在提议正式建立一个遗传学核心，作为计划项目赠款(PPG)的一部分，前额颞叶痴呆：基因类型和表型，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，并支持持续收集和储存这些家庭的DNA。将对与FTD相关的已知基因进行有限的遗传分析，以确定突变。最后，与临床相关的基因测试将被转移到临床(CLIA批准)实验室。明确定义的FTD队列的收集和/或新突变的识别将支持项目2中的基因发现，有助于推进项目1中FTD的临床特征，使FTD能够进行详细的生化和免疫组织化学分析(项目3)，导致产生新的疾病动物模型(项目2和4)，并作为神经病理学核心中经病理诊断的FTD病例的遗传分析的资源，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。

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.