GENETICS CORE

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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.