Mutations

MAPT R5H

Overview

Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity, Alzheimer's Disease : Not Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Genomic Mutation Name (MET1): g.75756G>A
Genomic Mutation Name (NT1): g.72930G>A
dbSNP ID: rs63750959
Coding/Non-Coding: Coding
Genomic Region: Exon 1
Mutation Type: Point, Missense
Codon Change: CGC to CAC

Findings

Initially associated with frontotemporal dementia, the role of this variant is currently unclear, and it may be benign.

This variant was first identified in an 81-year-old man who was diagnosed with probable familial FTD. He started to experience amnesia and disorientation at age 75. He exhibited no personality changes, aggressive behavior, or parkinsonism, but became nearly mute and had rigidity of the upper extremities by the time of his death at age 81. An elder brother had died at age 86 with dementia, but DNA was not available for analysis and segregation with disease could not be shown. The mutation was absent in 54 controls (Hayashi et al., 2002).

The R5H variant has also been reported in a large-scale screening study of individuals and families affected by late-onset Alzheimer's disease. The variant was found in one European family; however, it did not segregate with disease. Only one of five mutation carriers had a diagnosis of AD, and a noncarrier had the disease as well. Therefore, this rare variant is unlikely to contribute significantly to AD pathogenesis (Cruchaga et al., 2012).

Neuropathology

CT scan of the proband with FTD showed severe atrophy of both temporal lobes. Postmortem analysis showed neuronal loss in the frontal and temporal lobes as well as widespread tau deposits predominantly in glia. Extensive deposition of Sarkosyl-insoluble tau filaments composed of 4-repeat (4R) tau, as well as straight tubules reminiscent of progressive supranuclear palsy, were also observed (Hayashi et al., 2002).

Biological Effect

This mutation reduces tau's ability to promote microtubule assembly and promotes fibril formation in vitro (Hayashi et al., 2002). It was predicted to be "probably damaging" in silico by PolyPhen2 (Cruchaga et al., 2012).

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References

Paper Citations

  1. . Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol. 2002 Apr;51(4):525-30. PubMed.
  2. . Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012;7(2):e31039. PubMed.

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol. 2002 Apr;51(4):525-30. PubMed.

Other mutations at this position

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