Mutation in the tau gene in familial multiple system tauopathy with presenile dementia

Maria Grazia Spillantini, Jill R. Murrell, Michel Goedert, Martin R. Farlow, Aaron Klug, Bernardino Ghetti

Research output: Contribution to journalArticle

1213 Scopus citations


Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease with an abundant filamentous tau protein pathology. It belongs to the group of familial frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17), a major class of inherited dementing disorders whose genetic basis is unknown. We now report a G to A transition in the intron following exon 10 of the gene for microtubule- associated protein tau in familial MSTD. The mutation is located at the 3' neighboring nucleotide of the GT splice-donor site and disrupts a predicted stem-loop structure. We also report an abnormal preponderance of soluble tau protein isoforms with four microtubule-binding repeats over isoforms with three repeats in familial MSTD. This most likely accounts for our previous finding that sarkosyl-insoluble tau protein extracted from the filamentous deposits in familial MSTD consists only of tau isoforms with four repeats. These findings reveal that a departure from the normal ratio of four-repeat to three-repeat tau isoforms leads to the formation of abnormal tau filaments. The results show that dysregulation of tau protein production can cause neurodegeneration and imply that the FTDP-17 gene is the tau gene. This work has major implications for Alzheimer's disease and other tauopathies.

Original languageEnglish (US)
Pages (from-to)7737-7741
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number13
StatePublished - Jun 23 1998


  • Alternative mRNA splicing
  • Four-repeat tau isoforms
  • Frontotemporal dementia
  • Microtubule binding
  • Tau filaments

ASJC Scopus subject areas

  • Genetics
  • General

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