Genetic etiology of Fronto-Temporal Dementia

National Institute On Aging

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Abstract

During the last fiscal year, we have completed two projects that are directly relevant to FTD. First, the progranulin (PGRN) gene was sequenced in 134 Italian sporadic patients and 12 familial cases. Mutations in this gene has been previously identified as a cause of ubiquitin-positive FTD, but the role of this gene in the causation of ALS and ALS-FTD is unclear. Mutational screening revealed a heterozygous change (p.S120Y) in a patient diagnosed with sporadic ALS-FTD. This change was identical to one that we had previously identified in another ALS-FTD patient (cf Schymick et al., J Neurol Neurosurg Psychiatry. 2007;78:754-6). Haplotype analysis showed a conserved PGRN region among these two subjects consistent with common ancestor allele. This finding confirms that the missence mutation p.S120Y variant causes degeneration of frontal and temporal lobe neurons, as well as motor neurons (i.e. ALS-FTD) in rare cases. In the second project, a large scale two-stage linkage disequilibrium mapping approach was undertaken of the chromosome 9p21 region which has been previously linked to FTD, ALS and ALS-FTD phenotypes. An association of ubiquitin associated protein 1 (UBAP1;OR 1.42 95% CI 1.08-1.88, P=0.013) was identified and then replicated in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04-1.69, P=0.022), the USA (OR 1.4 95% CI 1.02-1.92, P=0.032), but not in a Spanish cohort (OR 1.45 95% CI 0.97-2.17, P=0.064) or in a cohort from London (OR 0.99 95% CI 0.72-1.37, P=0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, a case of familial FTD was identified that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. This data identified UBAP1 as a potential genetic risk factor for FTD. In summary, the current year has been successful in identifying genetic variants important in the pathogenesis of FTD using candidate gene approaches. Each of the two studies employed large cohorts of research subjects, and utilized the sequencing and genotyping facilities available within the Laboratory of Neurogenetics, NIA.