Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr17:44095989 G>A
dbSNP ID: rs63750095
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGC to AGC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This mutation was described in a single individual. The proband developed personality and behavioral changes at age 22 and died with severe cognitive impairment and parkinsonian symptoms at age 36. The mutation was not found in control individuals, nor was it present in the unaffected parents of the proband. None of proband's six siblings had symptoms of frontotemporal dementia. It was postulated that the G335S mutation may be a de novo event in the proband or the result of germline mosaicism in one of his parents (Spina et al., 2007).

Neuropathology

The proband's brain showed degeneration of the frontal and temporal lobes of the cerebral cortex, including a severe “knife edge” atrophy of the frontal and temporal gyri with thinning of the cortical ribbon. Severe degenerative changes were also present in the hippocampus and several subcortical regions, including the substantia nigra. This was accompanied by an extensive deposition of tau and the presence of neurofibrillary tangles and neuropil threads. Pick bodies were not observed. Abundant tau-positive inclusions were present in neurons and glia in the frontotemporal cortex, hippocampus, and brainstem. Sarkosyl-insoluble tau showed paired helical and straight filaments, as well as more irregular rope-like filaments (Spina et al., 2007).

Biological Effect

The G335S mutation greatly reduces the ability of tau to promote microtubule assemby (Spina et al., 2007).

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References

Paper Citations

1. Spina S, Murrell JR, Yoshida H, Ghetti B, Bermingham N, Sweeney B, Dlouhy SR, Crowther RA, Goedert M, Keohane C. The novel Tau mutation G335S: clinical, neuropathological and molecular characterization. Acta Neuropathol. 2007 Apr;113(4):461-70. Epub 2006 Dec 22 PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database