Mutations

MAPT G272V

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Genomic Mutation Name (MET1): g.110063G>T
Genomic Mutation Name (NT1): g.107237G>T
dbSNP ID: rs63750376
Coding/Non-Coding: Coding
Genomic Region: Exon 9
Mutation Type: Point, Missense
Codon Change: GGC to GTC
Research Models: 1

Findings

This mutation was identified in a large Dutch kindred originally described as having hereditary Pick's disease (see pedigree in Groen and Endtz, 1982). The family, known as HFTD2, had at least 34 affected individuals over seven generations. The mean age of onset in the family was 47 years. Presenting symptoms generally included changes in behavior, including disinhibition, aggression, and obsessional behavior (Heutink et al., 1997). Postmortem analysis confirmed the diagnosis of frontotemporal dementia in 15 individuals (Hutton et al., 1998).

Neuropathology

Multiple cases from the HFTD2 kindred have been examined neuropathologically. Severe frontotemporal lobe atrophy was commonly observed, as well as neuronal loss in the hippocampus and caudate nucleus. "Ballooned cells" were observed in the cortex and basal ganglia, as well as tau-positive inclusions in multiple cortical and subcortical areas (Heutink et al., 1997). A neuropathological study of three cases, aged 54, 56, and 57 at time of death, showed severe loss of neurons and gliosis in the frontal and temporal cortex, and to a lesser extent in the parietal cortex. Neuronal loss was also observed in the hippocampus. The caudate nucleus was degenerated and there was a severe loss of pigmented cells in the substantia nigra. In one case, a few Pick bodies were observed (Spillantini et al., 1998).

Biological Effect

This mutation produces tau proteins that are more favorable substrates for phosphorylation by brain protein kinases than wild-type tau isoforms (Alonso et al., 2004).

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References

Paper Citations

  1. . Hereditary Pick's disease: second re-examination of the large family and discussion of other hereditary cases, with particular reference to electroencephalography, a computerized tomography. Brain. 1982 Sep;105 (Pt 3):443-59. PubMed.
  2. . Hereditary frontotemporal dementia is linked to chromosome 17q21-q22: a genetic and clinicopathological study of three Dutch families. Ann Neurol. 1997 Feb;41(2):150-9. PubMed.
  3. . Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.
  4. . Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol. 1998 Nov;153(5):1359-63. PubMed.
  5. . Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem. 2004 Aug 13;279(33):34873-81. Epub 2004 Jun 9 PubMed.

Further Reading

Papers

  1. . Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem. 2004 Aug 13;279(33):34873-81. Epub 2004 Jun 9 PubMed.
  2. . Hereditary Pick's disease: second re-examination of the large family and discussion of other hereditary cases, with particular reference to electroencephalography, a computerized tomography. Brain. 1982 Sep;105 (Pt 3):443-59. PubMed.
  3. . Hereditary frontotemporal dementia is linked to chromosome 17q21-q22: a genetic and clinicopathological study of three Dutch families. Ann Neurol. 1997 Feb;41(2):150-9. PubMed.
  4. . High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet. 1999 Feb;64(2):414-21. PubMed.
  5. . Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol. 1999 Oct;46(4):617-26. PubMed.
  6. . Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain. 2003 Sep;126(Pt 9):2016-22. Epub 2003 Jul 22 PubMed.
  7. . Biochemical diagnosis of Alzheimer disease by measuring the cerebrospinal fluid ratio of phosphorylated tau protein to beta-amyloid peptide42. Arch Neurol. 2003 Sep;60(9):1202-6. PubMed.
  8. . Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology. Brain. 2005 Nov;128(Pt 11):2645-53. Epub 2005 Jul 13 PubMed.
  9. . Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol. 1999 Oct;46(4):617-26. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.