Mutations

MAPT R406W

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Genomic Mutation Name (MET1): g.137471C>T
Genomic Mutation Name (NT1): g.134649C>T
dbSNP ID: rs63750424
Coding/Non-Coding: Coding
Genomic Region: Exon 13
Mutation Type: Point, Missense
Codon Change: CGG to TGG
Research Models: 5

Findings

This mutation is associated with an autosomal-dominant form of dementia with widespread neurofibrillary tangles. The clinical presentation and course of the disease varies.

Some studies have reported a clinical phenotype with an early onset and rapid progression (e.g., Saito et al., 2002: onset at age 47 and mean age at death of 56.5 years), while others have observed a more insidious onset of dementia, with memory loss and personality changes in longer-lived patients (e.g., van Swieten et al, 1999: mean onset at 59.2 ± 5.5 years with mean duration of 12.7 ± 1.5 years). Two unrelated Japanese pedigrees have been reported, known as P3367 and P3048 (Ikeuchi et al., 2008). The former family had six affected individuals over three generations, with known ages of onset reported as 47 and 51. Affected individuals in this family had slowly progressive amnesia without apparent behavioral or language problems and met NINCDS-ADRDA criteria for probable AD (McKhann et al., 1984). The second family, P3048, had a slowly progressing form of the disease. Two siblings with a family history of AD, had symptom onset at ages 54 and 56 and both were alive at 17 and 13 years later. Parkinsonism and gaze disturbance have been noted in some families. A clinical phenotype closely resembling Alzheimer's disease also has been reported (Rademakers et al., 2003; Lindquist et al., 2008).

Neuropathology

Postmortem analysis showed mild symmetric frontotemporal atrophy with severe atrophy of the hippocampus. Tau-positive inclusions were seen including abundant neurofibrillary tangles. A pale substantia nigra was also noted (van Swieten et al., 1999).

Biological Effect

This mutation alters a highly conserved residue near the C-terminus of the tau protein, outside of the microtubule-binding repeats. Tau proteins with this mutation have a reduced ability to promote microtubule assembly, suggesting partial loss of function (Hasagawa et al., 1998).

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References

Paper Citations

  1. . Early-onset, rapidly progressive familial tauopathy with R406W mutation. Neurology. 2002 Mar 12;58(5):811-3. PubMed.
  2. . Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol. 1999 Oct;46(4):617-26. PubMed.
  3. . Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord. 2008;26(1):43-9. Epub 2008 Jun 28 PubMed.
  4. . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
  5. . Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe. Hum Mutat. 2003 Nov;22(5):409-11. PubMed.
  6. . Alzheimer disease-like clinical phenotype in a family with FTDP-17 caused by a MAPT R406W mutation. Eur J Neurol. 2008 Apr;15(4):377-85. Epub 2008 Feb 16 PubMed.
  7. . Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett. 1998 Oct 23;437(3):207-10. PubMed.

Further Reading

Papers

  1. . Molecular analysis of mutant and wild-type tau deposited in the brain affected by the FTDP-17 R406W mutation. Am J Pathol. 2001 Feb;158(2):373-9. PubMed.
  2. . The tau R406W mutation causes progressive presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord. 2004;17(4):298-301. PubMed.
  3. . 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.
  4. . Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009 Aug;76(2):205-9. Epub 2009 Jul 29 PubMed.
  5. . Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement Geriatr Cogn Disord. 2008;26(1):43-9. Epub 2008 Jun 28 PubMed.
  6. . Familial presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord. 2004;17(4):287-92. PubMed.
  7. . 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.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Neurodegenerative diseases with cytoskeletal pathology: a biochemical classification. Ann Neurol. 1997 Oct;42(4):541-4. PubMed.
  2. . Autosomal dominant dementia with widespread neurofibrillary tangles. Ann Neurol. 1997 Oct;42(4):564-72. 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.