Overview

Pathogenicity: Other Tauopathy : Uncertain Significance
Clinical Phenotype: Corticobasal Degeneration
Position: (GRCh38/hg38):Chr17:46024073 A>C
Position: (GRCh37/hg19):Chr17:44101439 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAT to CAT
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 13

Findings

This mutation was identified via sequence analysis of the entire coding region of MAPT in 109 pathologically confirmed cases of corticobasal degeneration. The clinical history of the mutation carrier begins with the development of mood and memory problems at age 63. One year later, the patient developed mild cognitive impairment and parkinsonism. The disease progressed rapidly and she developed severe memory impariment, an unsteady gait, a hand tremor, and became mute. She died at age 67 (Kouri et al., 2014).

Neuropathology

Postmortem examination of the patient's brain showed mild atrophy of the superior frontal cortex and enlargement of the lateral ventricles. There was marked loss of neuromelanin in the midbrain and abundant 4R tau-positive astrocytic plaques and numerous threads in the gray and white matter. Abundant ballooned neurons in the superior frontal cortex and significant TDP-43 pathology, especially the basal ganglia (Kouri et al., 2014).

Biological Effect

In a brain sample, there was an increase in the 4R/3R tau mRNA ratio. Recombinant tau with the N410H mutation showed a marked increase in tau filament formation compared with wild-type tau, as well as a decreased rate of microtubule assembly and a reduction in the extent of total microtubule polymerization (Kouri et al., 2014).

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References

Paper Citations

1. Kouri N, Carlomagno Y, Baker M, Liesinger AM, Caselli RJ, Wszolek ZK, Petrucelli L, Boeve BF, Parisi JE, Josephs KA, Uitti RJ, Ross OA, Graff-Radford NR, DeTure MA, Dickson DW, Rademakers R. Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration. Acta Neuropathol. 2014 Feb;127(2):271-82. PubMed.

Further Reading

No Available Further Reading