Overview

Pathogenicity: Frontotemporal Dementia : Uncertain Significance
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:45971888 G>A
Position: (GRCh37/hg19):Chr17:44049254 G>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGA to AGA
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 2

Findings

This mutation was identified in an individual diagnosed with the behavioral variant of frontotemporal dementia. The proband showed progressive deterioration of behavior and cognition and frontal and temporal atrophy by MRI. She had a family history of dementia, but DNA was not available from her father and two siblings (deceased), and therefore pathogenicity could not be determined. The G55R mutation was absent in 150 neurologically healthy subjects, aged more than 65 years, as well as in 152 patients with clinically diagnosed familial and sporadic FTD (Iyer et al., 2013).

Neuropathology

Unknown. MRI showed frontal and temporal atrophy.

Biological Effect

This mutation, in the alternatively spliced exon 2 of MAPT, causes a substitution of arginine for glycine in a highly conserved, acidic region of the protein. In vitro studies showed that the 4-repeat (4R) isoform of tau with the G55R mutation nucleates microtubule assembly more effectively than wild-type 4R tau. This effect appears to be isoform-specific in that no difference in microtubule nucleation was seen when the mutation was introduced in 3R tau. The G55R mutation does not affect the dynamics of microtubule lengthening or shortening (Iyer et al., 2013).

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References

Paper Citations

1. Iyer A, Lapointe NE, Zielke K, Berdynski M, Guzman E, Barczak A, Chodakowska-Żebrowska M, Barcikowska M, Feinstein S, Zekanowski C. A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered Tau function. PLoS One. 2013;8(9):e76409. Epub 2013 Sep 27 PubMed.

Further Reading

No Available Further Reading