Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46018624 G>C
Position: (GRCh37/hg19):Chr17:44095990 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGC to GCC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This mutation was found in an individual with frontotemporal dementia with a very young age of onset (Ando et al., 2020). Symptoms of declining attention, concentration, and organizational skills were first noted when the carrier was 14 years old, followed by anxiety, panic attacks, and the development of an obsession with time. He was diagnosed originally with a schizophrenic disorder, but worsening cognitive and behavioral symptoms led to referral to a neurology clinic at age 24. Imaging studies at this time revealed frontotemporal atrophy. The patient was institutionalized a year later, and he died at age 34.

Genotyping revealed a novel mutation within the MAPT gene, causing a glycine-to-alanine substitution at amino acid 335 (numbering for the 441 amino acid isoform of tau). The mutation was not found in the proband’s parents, suggesting that it arose de novo.

Although this variant has been described in only a single individual, Alzforum classifies it as pathogenic based on the occurrence of two other missense mutations within this codon that have been identified in patients with FTD.

Neuropathology

Postmortem examination of the brain revealed severe atrophy of the frontal and anterior temporal lobes.

Neurofibrillary tangles (NFTs) were present in frontal, temporal, and parietal cortices, hippocampal field CA1 and the subiculum, the substantia nigra, and the pontine and olivary nuclei in the brainstem. NFTs stained with antibodies against both 3R- and 4R-tau and appeared as either straight or paired helical filaments when observed with the electron microscope. (Biochemical analysis confirmed the presence of both 3R- and 4R-tau in sarkosyl-insoluble extracts of the frontal cortex.)

Astrogliosis was notable in the frontal cortex and in the subependymal zone. Some astrocytes contained  deposits composed of 4R tau.

Pronounced neuron loss occurred in the frontal and temporal cortices and in the substantia nigra.

Biological Effect

Amino acid 335 is located within the third microtubule-binding domain of tau. While the effect of the G335A mutation is unknown, the other mutations at this position, G335S (Spina et al., 2007) and G335V (Neumann et al., 2005), have been shown to reduce the ability of tau to promote microtubule assembly.

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References

Paper Citations

1. Ando K, Ferlini L, Suain V, Yilmaz Z, Mansour S, Le Ber I, Bouchard C, Leroy K, Durr A, Clot F, Sarazin M, Bier JC, Brion JP. de novo MAPT mutation G335A causes severe brain atrophy, 3R and 4R PHF-tau pathology and early onset frontotemporal dementia. Acta Neuropathol Commun. 2020 Jun 29;8(1):94. PubMed.
2. Spina S, Murrell JR, Yoshida H, Ghetti B, Bermingham N, Sweeney B, Dlouhy SR, Crowther RA, Goedert M, Keohane C. The novel Tau mutation G335S: clinical, neuropathological and molecular characterization. Acta Neuropathol. 2007 Apr;113(4):461-70. Epub 2006 Dec 22 PubMed.
3. Neumann M, Diekmann S, Bertsch U, Vanmassenhove B, Bogerts B, Kretzschmar HA. Novel G335V mutation in the tau gene associated with early onset familial frontotemporal dementia. Neurogenetics. 2005 May;6(2):91-5. Epub 2005 Mar 12 PubMed.

Further Reading

No Available Further Reading