Mutations

MAPT Q336R

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Genomic Mutation Name (MET1): g.132037A>G
Genomic Mutation Name (NT1): g.129217A>G
dbSNP ID: rs63750573
Coding/Non-Coding: Coding
Genomic Region: Exon 12
Mutation Type: Point, Missense
Codon Change: CAG to CGG

Findings

The proband was a 68‐year‐old man who died following a 10-year history of changes in memory, language, behavior, and personality. He had a family history of a similar dementing disorder, consistent with autosomal dominant transmission. This mutation is thought to be pathogenic because it was identified in an individual with a clinical phenotype of frontotemporal dementia who had a family history of premature cognitive decline, although the genotypes of affected family members are unknown, so pathogenicity could not be determined. The Q336R mutation was not found in 100 unaffected individuals  (Pickering-Brown et al., 2004).

Neuropathology

Moderately severe atrophy of the frontal lobes and severe atrophy of the anterior temporal lobes, hippocampus, and amygdala were observed in the proband's brain. Although neuronal loss varied by region, in some areas neuronal loss and astrogliosis were extensive, leading to widespread spongiosis and loss of cytoarchitecture. Hyperphosphorylated tau accumulated in swollen (Pick) cells and intraneuronal inclusions (Pick bodies) were seen containing both 3‐repeat (3R) and 4‐repeat (4R) tau. Neurons within the frontal cortex contained neurofibrillary tangle‐like structures (both straight and twisted tubules), as well as Pick bodies in which the filaments were short and randomly oriented (Pickering-Brown et al., 2004).

Biological Effect

The Q336R is associated with an increase in tau fibrillogenesis. In contrast to most MAPT missense mutations, Q336R increased, rather than decreased, the ability of mutant tau to promote microtubule assembly (Pickering-Brown et al., 2004).

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References

Paper Citations

  1. . Frontotemporal dementia with Pick-type histology associated with Q336R mutation in the tau gene. Brain. 2004 Jun;127(Pt 6):1415-26. Epub 2004 Mar 26 PubMed.

Further Reading

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Primary Papers

  1. . Frontotemporal dementia with Pick-type histology associated with Q336R mutation in the tau gene. Brain. 2004 Jun;127(Pt 6):1415-26. Epub 2004 Mar 26 PubMed.