Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46018615 C>T
Position: (GRCh37/hg19):Chr17:44091687 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to TCA
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 11

Findings

This variant has been described in a French family with an unusual and heterogenous clinical phenotype (Deramecourt et al., 2012).

The proband developed a slowly progressing speech disorder starting at the age of 60. Her first symptom was a change in the tone of her voice, which became hypernasal. She developed difficulty swallowing around 10 years later, and was considered to have a syndrome of progressive anarthria (loss of motor ability that enables speech). Up until her death at age 85, her cognition and behavior were unaffected.

The proband's two sons developed a form of frontotemporal dementia characterized by behavioral and semantic impairments. At 48 and 50 years of age they developed increasing forgetfulness, progressive prosopagnosia ("face blindness"), specific semantic impairments, and behavioral changes such as self-neglect and compulsive eating. One of the brothers reportedly lost the ability to "differentiate good wines from bad ones." MRI in both brothers showed bilateral anterior temporal lobe atrophy, consistent with a temporal variant of frontotemporal lobar degneration.

All three affected family members were mutation carriers. DNA was not available from additional family members to confirm segregation with disease.

Neuropathology

Neuropathological examination of the proband showed atrophy in primary motor and premotor cortices, along with spongiosis, gliosis, and neuronal loss. Neuronal tau-positive lesions were present, especially in the dentate gyrus. The lesions contained both 3-repeat (3R) and 4-repeat (4R) tau isoforms and resembled Pick bodies. Some neurofibrillary tangles were also observed. Immunohistochemistry for TDP-43, prion protein, and α-synuclein were negative (Deramecourt et al., 2012).

Biological Effect

This mutation affects a highly conserved amino acid in the third microtubule binding domain of the protein. The mutation is associated with a decreased capacity to bind microtubules (Deramecourt et al., 2012).

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References

Paper Citations

1. Deramecourt V, Lebert F, Maurage CA, Fernandez-Gomez FJ, Dujardin S, Colin M, Sergeant N, Buée-Scherrer V, Clot F, Ber IL, Brice A, Pasquier F, Buée L. Clinical, neuropathological, and biochemical characterization of the novel tau mutation P332S. J Alzheimers Dis. 2012;31(4):741-9. PubMed.

Further Reading

No Available Further Reading