From genotype to phenotype: A clinical, pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation

Frontotemporal dementia is a heterogeneous, often inherited disorder that t ypically presents with the insidious onset of behavioral and personality ch anges, Two genetic loci have been identified and mutations in tau have been causally implicated in a subset of families linked to one of these loci on chromosome 17q21-22, In this study, linkage analysis was performed in a la rge pedigree, the MN family, suggesting chromosome 17q21-22 linkage. Mutati onal analysis of the tau coding region identified a C-to-T change in exon 1 0 that resulted in the conversion of proline to a leucine (P301L) that segr egated with frontotemporal dementia in this family, The clinical and pathol ogical findings in the MN family emphasize the significant overlap between Pick's disease, corticobasal degeneration, and frontotemporal dementia and challenge some of the current dogma surrounding this condition, Pathologica l studies of two brains from affected members of Family MN obtained at auto psy demonstrate numerous tau-positive inclusions that were most prominent i n the frontal lobes, anterior temporal lobes, and brainstem structures, as well as Pick-like bodies and associated granulovacuolar degeneration. These Pick-like bodies were observed in 1 patient with motor neuron disease. Bec ause exon 10 is present only in tau mRNA coding for a protein with four mic rotubule binding repeats (4R), this mutation should selectively affect 4Rta u isoforms. Indeed, immunoblotting demonstrated that insoluble 4Rtau is sel ectively aggregated in both gray and white matter of affected individuals, Although there was significant pathological similarity between the 2 cases, the pattern of degenerative changes and tau-positive inclusions was not id entical, suggesting that other genetic of epigenetic factors can significan tly modify the regional topology of neurodegeneration in this condition.