Overview

Pathogenicity: Frontotemporal Dementia : Uncertain Significance
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46010421 C>G
Position: (GRCh37/hg19):Chr17:44087787 C>G
dbSNP ID: rs63750162
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift
Codon Change: C to G
Genomic Region: Intron 10

Findings

This mutation was detected in one individual (Pedigree B) who exhibited characteristic features of frontotemporal dementia. The proband presented with cognitive impairment and behavioral changes at age 52. The IVS10+19 mutation was absent in the proband's unaffected mother and 200 controls (Stanford et al., 2003).

Neuropathology

A CT scan of the proband's brain showed atrophy, especially in the frontal lobe. A SPECT scan showed frontal hypoperfusion, particularly on the left (Stanford et al., 2003).

Biological Effect

Exon‐trapping experiments showed that this intronic mutation alters the splicing of exon 10, resulting in a greater proportion of tau isoforms with three microtubule-binding domains (3R tau). Microtubule-binding experiments showed reduced microtubule assembly with increasing amounts of 3R and decreasing amounts of 4R tau. This observation is consistent with a pathogenic role for this mutation (Stanford et al., 2003).

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References

Paper Citations

1. Stanford PM, Shepherd CE, Halliday GM, Brooks WS, Schofield PW, Brodaty H, Martins RN, Kwok JB, Schofield PR. Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia. Brain. 2003 Apr;126(Pt 4):814-26. PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database