Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP3
Clinical Phenotype Studied: bvFTD
Position: (GRCh38/hg38):Chr17:46018624 G>T
Position: (GRCh37/hg19):Chr17:44095990 G>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750905
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGC to GTC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This mutation was identified in a German family with early onset frontotemporal dementia (Neumann et al., 2005). At the age of 25, the proband presented with personality changes (lack of interest, unsocial behavior, and personal neglect) and was initially diagnosed with schizophrenia. Later the proband developed cognitive impairment with specific deficits in attention and executive functions. A subsequent report classified the disorder as the behavioral variant of FTD (Chu et al., 2022). The mean age at onset in this family was 25.4 years (Neumann et al., 2005). 

Of note, the mutation was identified in the proband and an affected second cousin. Two unaffected family members were non-carriers in the same generation as the parents of the carriers. However, their ages were not reported, and thus, their genotype cannot serve as evidence for the mutation’s co-segregation with disease.

In an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature, one family, including six presumed carriers, was reported (Moore et al., 2020, suppl tables 5-6). Data included both confirmed mutation carriers and family members who were assumed to be carriers based on their clinical phenotype. Mean age at onset was 25.4 years and mean age at death 36.5 years. One of the presumed carriers was diagnosed with bvFTD, and five with dementia not otherwise specified. The family reported in this study may be the same family described by Neumann and colleagues (Neumann et al., 2005).

This variant was absent from the gnomAD public variant database (gnomAD v4.1.1, Apr 2024).

Neuropathology

Postmortem analysis is unavailable.

Biological Effect

Amino acid 335 is located within the third microtubule-binding repeat domain of tau. The G335V mutation resulted in a reduced ability of tau containing either three microtubule-binding repeats (3R) or four (4R) to promote microtubule assembly in vitro (Neumann et al., 2005; Spina et al., 2007). Consistent with these findings, tau binding to paclitaxel-stabilized microtubules was decreased in HEK293T cells expressing either 3R mutant tau (Xia et al., 2023) or 4R mutant tau (Xia et al., 2019) compared to cells expressing the wild-type isoforms.

The effects of G355V on tau aggregation remain unclear. One in vitro study reported the mutation led to an increased heparin-induced assembly of recombinant tau into filaments, as assessed by thioflavin-S fluorescence (Neumann et al., 2005). However, in another in vitro study, no significant effect on heparin-induced aggregation of 3R and 4R tau was observed using thioflavin T fluorescence and electron microscopy (Spina et al., 2007). Experiments in cultured cells revealed modest aggregation of the 0N4R mutant protein in either the presence or absence of K18, a tau fragment that can seed aggregation (Xia et al., 2019), and no effects on aggregation in the 0N3R tau isoform (Xia et al., 2023).

This variant's PHRED-scaled CADD score (32), which integrates diverse information in silico, was well above the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Pathogenic

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. 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.
2. Chu M, Liu L, Nan H, Jiang D, Wang Y, Rosa-Neto P, Piao Y, Wu L. Extremely Early-Onset Frontotemporal Dementia: A Case Report and Literature Review. J Alzheimers Dis. 2022;90(3):1139-1151. PubMed.
3. Moore KM, Nicholas J, Grossman M, McMillan CT, Irwin DJ, Massimo L, Van Deerlin VM, Warren JD, Fox NC, Rossor MN, Mead S, Bocchetta M, Boeve BF, Knopman DS, Graff-Radford NR, Forsberg LK, Rademakers R, Wszolek ZK, van Swieten JC, Jiskoot LC, Meeter LH, Dopper EG, Papma JM, Snowden JS, Saxon J, Jones M, Pickering-Brown S, Le Ber I, Camuzat A, Brice A, Caroppo P, Ghidoni R, Pievani M, Benussi L, Binetti G, Dickerson BC, Lucente D, Krivensky S, Graff C, Öijerstedt L, Fallström M, Thonberg H, Ghoshal N, Morris JC, Borroni B, Benussi A, Padovani A, Galimberti D, Scarpini E, Fumagalli GG, Mackenzie IR, Hsiung GR, Sengdy P, Boxer AL, Rosen H, Taylor JB, Synofzik M, Wilke C, Sulzer P, Hodges JR, Halliday G, Kwok J, Sanchez-Valle R, Lladó A, Borrego-Ecija S, Santana I, Almeida MR, Tábuas-Pereira M, Moreno F, Barandiaran M, Indakoetxea B, Levin J, Danek A, Rowe JB, Cope TE, Otto M, Anderl-Straub S, de Mendonça A, Maruta C, Masellis M, Black SE, Couratier P, Lautrette G, Huey ED, Sorbi S, Nacmias B, Laforce R Jr, Tremblay ML, Vandenberghe R, Damme PV, Rogalski EJ, Weintraub S, Gerhard A, Onyike CU, Ducharme S, Papageorgiou SG, Ng AS, Brodtmann A, Finger E, Guerreiro R, Bras J, Rohrer JD, FTD Prevention Initiative. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2020 Feb;19(2):145-156. Epub 2019 Dec 3 PubMed.
4. 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.
5. Xia Y, Bell BM, Kim JD, Giasson BI. Tau mutation S356T in the three repeat isoform leads to microtubule dysfunction and promotes prion-like seeded aggregation. Front Neurosci. 2023;17:1181804. Epub 2023 May 25 PubMed.
6. Xia Y, Sorrentino ZA, Kim JD, Strang KH, Riffe CJ, Giasson BI. Impaired tau-microtubule interactions are prevalent among pathogenic tau variants arising from missense mutations. J Biol Chem. 2019 Nov 29;294(48):18488-18503. Epub 2019 Oct 24 PubMed.

Further Reading

No Available Further Reading