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: 4

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. 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

Mild symmetric frontotemporal atrophy. Severe atrophy of hippocampus with abundant neurofibrillary tangles and pale substantia nigra. Tau-positive inclusions (van Swieten et al., 1999).

Biological Effect

This mutation alters a highly conserved residue near the C-terminus of the tau protein, outside 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. PubMed.
  4. . 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.
  5. . 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. PubMed.
  6. . 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. 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. 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. PubMed.
  6. . Familial presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord. 2004;17(4):287-92. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Neurodegenerative diseases with cytoskeletal pathology: a biochemical classification. Ann Neurol. 1997 Oct 01;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.