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

Ann Neurol. 1999 Jun;45(6):704-15. doi: 10.1002/1531-8249(199906)45:6<704::aid-ana4>;2-x.


Frontotemporal dementia is a heterogeneous, often inherited disorder that typically presents with the insidious onset of behavioral and personality changes. 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 large pedigree, the MN family, suggesting chromosome 17q21-22 linkage. Mutational analysis of the tau coding region identified a C-to-T change in exon 10 that resulted in the conversion of proline to a leucine (P301L) that segregated with frontotemporal dementia in this family. The clinical and pathological 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. Pathological studies of two brains from affected members of Family MN obtained at autopsy demonstrate numerous tau-positive inclusions that were most prominent in 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. Because exon 10 is present only in tau mRNA coding for a protein with four microtubule binding repeats (4R), this mutation should selectively affect 4Rtau isoforms. Indeed, immunoblotting demonstrated that insoluble 4Rtau is selectively 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 identical, suggesting that other genetic or epigenetic factors can significantly modify the regional topology of neurodegeneration in this condition.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Brain / pathology
  • Dementia / genetics*
  • Dementia / pathology
  • Frontal Lobe
  • Genetic Linkage / genetics
  • Genotype
  • Humans
  • Middle Aged
  • Mutation / genetics*
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Pedigree
  • Phenotype
  • Temporal Lobe
  • tau Proteins / analysis*


  • tau Proteins