Mutations

MAPT IVS10+12 C>T

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr17:'44087780 C>T
dbSNP ID: rs63750916
Coding/Non-Coding: Non-Coding
Mutation Type: Point
Codon Change: C to T
Genomic Region: Intron 10

Findings

This mutation was identified as the causative mutation in the Kumamoto pedigree, a Japanese kindred exhibiting frontotemporal dementia (Yasuda et al., 2000). The primary clinical characteristics were parkinsonism and dementia presenting in the fifth decade of life, with a mean age of onset of 53 years and a mean duration of illness of seven years (n=6).

Neuropathology

Brain tissue from affected individuals showed elevated exon 10 containing tau transcripts and 4R tau isoforms. Tau aggregates were observed in neurons and glial cells. Isolated tau filaments had twisted, ribbon-like morphology, and were comprised of hyperphosphorylated 4R tau (Yasuda et al 2000). Neuropathological findings for one member of this pedigree are described by Takamatsu et al., 1998.

Biological Effect

This mutation disrupts exon 10 alternative splicing, increasing the proportion of tau mRNA that includes exon 10 and resulting in overproduction of isoforms with four microtubule binding repeats (4R tau) (Yasuda et al., 2000).

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References

Paper Citations

  1. . 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. PubMed.
  2. . Selective expression of Ser 199/202 phosphorylated tau in a case of frontotemporal dementia. Dement Geriatr Cogn Disord. 1998 Mar-Apr;9(2):82-9. PubMed.

Further Reading

Papers

  1. . "Missing" tau mutation identified. Ann Neurol. 2000 Apr;47(4):417-8. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . 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. PubMed.

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