Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP3
Clinical Phenotype Studied: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46018645 A>T
Position: (GRCh37/hg19):Chr17:44096011 A>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750711
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to GTG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

The E342V mutation was identified in a woman with frontotemporal dementia and a family history of FTDP-17. Her presenting symptoms were expressive language difficulties and emotional lability, which became progressively worse over time. She became disoriented, confused, and mildly parkinsonian. She lost most spontaneous speech and died at the age of 55, about seven years after symptom onset (Lippa et al., 2000).

This variant is rare--it was absent from the gnomAD variant database (v.4.1.0, Apr 2024).

Neuropathology

Neuropathological analysis of the carrier’s brain revealed prominent frontotemporal neuron loss, cytoplasmic tau aggregates, paired helical tau filaments, increased 4-repeat (4R) tau mRNA resulting in a 4R:3R ratio greater than one. Moreover, 4R tau without exon 2 and exon 3 inserts (0N4R tau) was increased, while 1N4R and 2N4R tau isoforms were decreased (Lippa et al., 2000). Interestingly, despite the increase in 4R tau, only the 3R isoform was found in intraneuronal tau inclusions known as Pick bodies (de Silva et al., 2006). The 4R tau isoform was identified in astrocytes.

Biological Effect

As noted above, this variant appears to alter the splicing of tau resulting in increased levels of 0N4R tau (Lippa et al., 2000). It appears to have little or no effect on either tau aggregation or microtubule dynamics, however.

Mutant 0N4R tau did not fuel tau aggregation in a cell-based assay in which HEK393T cells expressing the mutation were incubated with preformed fibrils of either wildtype or mutant aggregation-prone K18 tau fragments (Strang et al., 2018). Moreover, in an arachidonic acid-induced aggregation assay using recombinant 2N4R tau, E342V tau aggregated to the same extent as wildtype tau as assessed by light scattering and thioflavin S fluorescence (Combs and Gamblin 2012). In the same study, kinetics measurements indicated moderate decreases in nucleation and elongation rates for mutant tau polymerization, whereas electron microscopy suggested a modest increase in tau polymerization. The authors concluded that, overall, mutant and wildtype tau behaved similarly.

The effects of E342V on microtubule dynamics were also minimal (Combs and Gamblin 2012). The total amount of 2N4R mutant tau polymerization was similar to that of the wildtype protein, with a modest increase in the rate of tubulin polymerization and a decrease in the lag time.

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (23.8), suggesting a deleterious effect (CADD v.1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Not Classified*

*This variant fulfilled several ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Paper Citations

1. Lippa CF, Zhukareva V, Kawarai T, Uryu K, Shafiq M, Nee LE, Grafman J, Liang Y, St George-Hyslop PH, Trojanowski JQ, Lee VM. Frontotemporal dementia with novel tau pathology and a Glu342Val tau mutation. Ann Neurol. 2000 Dec;48(6):850-8. PubMed.
2. de Silva R, Lashley T, Strand C, Shiarli AM, Shi J, Tian J, Bailey KL, Davies P, Bigio EH, Arima K, Iseki E, Murayama S, Kretzschmar H, Neumann M, Lippa C, Halliday G, MacKenzie J, Ravid R, Dickson D, Wszolek Z, Iwatsubo T, Pickering-Brown SM, Holton J, Lees A, Revesz T, Mann DM. An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies. Acta Neuropathol. 2006 Apr;111(4):329-40. Epub 2006 Mar 22 PubMed.
3. Strang KH, Croft CL, Sorrentino ZA, Chakrabarty P, Golde TE, Giasson BI. Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies. J Biol Chem. 2018 Feb 16;293(7):2408-2421. Epub 2017 Dec 19 PubMed.
4. Combs B, Gamblin TC. FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions. Biochemistry. 2012 Oct 30;51(43):8597-607. Epub 2012 Oct 18 PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database