A novel mutation at position +12 in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto)

Ann Neurol. 2000 Apr;47(4):422-9.


Exonic and intronic mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe a new mutation, consisting of a C-to-T transition at position +12 of the intron following exon 10 of the tau gene in the Kumamoto pedigree, showing frontotemporal dementia. The mutation caused a marked reduction in melting temperature of the tau exon 10-splicing regulatory element RNA and a large increase in exon 10-containing transcripts. Brain tissue from affected individuals showed an abnormal preponderance of exon 10-containing transcripts that was reflected at the protein level by an overproduction of tau isoforms with four microtubule-binding repeats. Immunostaining revealed the presence of tau aggregates in degenerating neurons and glial cells. Isolated tau filaments had a twisted ribbon-like morphology and were made of hyperphosphorylated four-repeat tau isoforms. The additional mutation located dose to the splice-donor site of the intron following exon 10 of the tau gene supports the view that intronic mutations exercize their pathogenic effect by destabilizing RNA secondary structure.

Publication types

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

MeSH terms

  • Brain / pathology
  • Brain Chemistry / genetics
  • DNA Mutational Analysis
  • Dementia / genetics*
  • Dementia / pathology
  • Detergents
  • Exons / genetics
  • Family Health
  • Female
  • Hot Temperature
  • Humans
  • Introns / genetics*
  • Male
  • Microscopy, Electron
  • Middle Aged
  • Pedigree
  • Point Mutation*
  • RNA Splicing / physiology
  • RNA, Messenger / analysis
  • Regulatory Sequences, Nucleic Acid / genetics
  • Sarcosine / analogs & derivatives
  • Solubility
  • tau Proteins / analysis
  • tau Proteins / genetics*
  • tau Proteins / ultrastructure


  • Detergents
  • RNA, Messenger
  • tau Proteins
  • sarkosyl
  • Sarcosine