Overview

Pathogenicity: Frontotemporal Dementia : Uncertain Significance, Parkinson's Disease : Not Classified
Clinical Phenotype: Frontotemporal Dementia, Parkinson's Disease
Position: (GRCh38/hg38):Chr17:46024125 C>T
Position: (GRCh37/hg19):Chr17:44101491 C>T
dbSNP ID: rs63750991
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to ATG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 13

Findings

The T427M mutation was first described in an Italian patient with a family history of dementia and clinical features typical of frontotemporal dementia. Starting at age 60 she developed language disturbance and personality changes with apathy. Although her cognition was affected later in the course of the disease, her memory and spatial skills were relatively spared. The patient died at age 67 and no autopsy was performed. The mutation was absent in the proband's two unaffected sisters (ages 64 and 53), as well as in 150 control individuals and 150 other people with dementia (Giaccone et al., 2005).

This variant was later detected in one out of 188 cases with Parkinson’s disease (Schulte et al., 2015). This individual had apparently idiopathic PD; however, family history information was not available. This individual developed symptoms at age 66, starting with resting tremor. Later symptoms included bradykinesia, rigor, and postural instability. Dementia was not present. This variant was absent in 188 cases of PD with dementia and in 376 elderly controls. Note that this study reported the variant as T762M in reference to tau isoform G (P10636-9), aka isoform 6 (NP_001116538), which is 776 amino acids long. It is numbered here as T427M to reflect its position in tau isoform F (P10636-8), which is 441 amino acids in length and conventionally used for describing mutations in MAPT.

Neuropathology

Unknown. MRI showed moderate frontotemporal atrophy, more prominent on the left (Giaccone et al., 2005).

Biological Effect

Unknown.

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References

Paper Citations

1. Giaccone G, Rossi G, Farina L, Marcon G, Di Fede G, Catania M, Morbin M, Sacco L, Bugiani O, Tagliavini F. Familial frontotemporal dementia associated with the novel MAPT mutation T427M. J Neurol. 2005 Dec;252(12):1543-5. Epub 2005 Jun 6 PubMed.
2. Schulte EC, Fukumori A, Mollenhauer B, Hor H, Arzberger T, Perneczky R, Kurz A, Diehl-Schmid J, Hüll M, Lichtner P, Eckstein G, Zimprich A, Haubenberger D, Pirker W, Brücke T, Bereznai B, Molnar MJ, Lorenzo-Betancor O, Pastor P, Peters A, Gieger C, Estivill X, Meitinger T, Kretzschmar HA, Trenkwalder C, Haass C, Winkelmann J. Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.

External Citations

1. P10636-9
2. NP_001116538

Further Reading

No Available Further Reading