Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46018716 G>A
Position: (GRCh37/hg19):Chr17:44096082 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 12

Findings

This mutation was identified in an Italian family known as “DM” in which two individuals over two generations had symptoms consistent with frontotemporal dementia. The proband began experiencing symptoms at age 52, including bizarre behavior and personality changes. She later developed apathy and aggressive behavior, followed by severe language and memory disturbances, apraxia, and bradykinesia. Her mother died at age 55 following an eight-year history of dementia with prominent behavioral disturbances. No additional family history was reported. The proband was a mutation carrier and her unaffected sister was not. In addition to MAPT, the progranulin gene, GRN, was screened, but no mutations were detected (Rossi et al., 2012).

Neuropathology

Unknown. MRI showed moderate to severe symmetrical cerebral atrophy, predominantly involving the frontal lobe with ventricular enlargement (Rossi et al., 2012).

Biological Effect

In vitro, mutant tau exhibited reduced ability to promote microtubule assembly compared with wild-type tau, but aggregation kinetics were similar to wild-type (Rossi et al., 2012). In addition, increased chromosomal instability and copy-number variations have been observed in lymphocytes and fibroblasts of mutation carriers (Rossi et al., 2013).

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References

Paper Citations

1. Rossi G, Bastone A, Piccoli E, Mazzoleni G, Morbin M, Uggetti A, Giaccone G, Sperber S, Beeg M, Salmona M, Tagliavini F. New mutations in MAPT gene causing frontotemporal lobar degeneration: biochemical and structural characterization. Neurobiol Aging. 2012 Apr;33(4):834.e1-6. Epub 2011 Sep 22 PubMed.
2. Rossi G, Conconi D, Panzeri E, Redaelli S, Piccoli E, Paoletta L, Dalprà L, Tagliavini F. Mutations in MAPT gene cause chromosome instability and introduce copy number variations widely in the genome. J Alzheimers Dis. 2013;33(4):969-82. PubMed.

Further Reading

No Available Further Reading