Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype Studied: Progressive Supranuclear Palsy, Parkinsonism
Position: (GRCh38/hg38):Chr17:46010395 G>T
Position: (GRCh37/hg19):Chr17:44087761 G>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63751391
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Missense
Codon Change: GGC to GTC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This mutation is associated with autosomal-dominant disorder similar to progressive supranuclear palsy (PSP), but with an earlier onset and shorter duration than typical PSP. It was first reported reported in a family with three affected family members over two generations. Starting at age 37, the proband developed akinetic-rigid syndrome, gait disturbance, and frequent falls, among other symptoms. She died at age 45. The two other affected family members had a similar age of onset (41 and late 30s) and age at death (45 and 41) (Ros et al., 2005).

A follow-up study extended these findings, including data collected across 26 years from six affected family members over 3 generations (Choumert et al., 2012). All six affected individuals carried the mutation, and the pattern of inheritance was consistent with autosomal dominant transmission. Unaffected non-carriers were not reported.
Clinical heterogeneity was observed, with four patients initially presenting with Richardson’s-like syndrome, including postural instability, early falls, paralysis of vertical gaze, and cognitive impairment, while two patients had a PSP-parkinsonism-like syndrome with unilateral bradykinesia and dystonia. Mean age at onset was 40 years and disease duration four years.

In an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature, two families, including six presumed carriers, were 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 38.5 years with a mean duration of disease of 4.6 years. All six affected individuals were classified as having PSP.

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

Neuropathology

Neuropathological analysis of the proband's brain showed atrophy of the mesencephalon, pons, striatum, and subthalamic nuclei. The substantia nigra was depigmented and showed neuronal loss, mild spongiosis, and gliosis. Ventricles were enlarged and there was mild atrophy of the frontotemporal cortex. Tau accumulations were seen in neurons and glia, including neurofibrillary tangles. The brain was noted to have an increase in 4-repeat (4R) isoforms of tau (Ros et al., 2005).

Biological Effect

As noted above, this variant increases 4R tau isoforms (Ros et al., 2005), and in a cell-based minigene splicing assay, G303V increased exon 10 inclusion (Tubeuf et al., 2020).

G303V also appears to increase tau oligomerization and reduce microtubule assembly. Aggregation of G303V tau has been evaluated in vitro using electron microscopy, a thioflavin S fluorescence assay, and a laser light scattering assay (Combs and Gamblin 2012). The light scattering assay showed a robust decrease, while the thioflavin S assay yielded unclear results. Examination of aggregates using electron microscopy revealed abundant oligomer formation, with more polymerization than wildtype tau, but little or no filament formation. G303V tau’s nucleation rate was substantially increased compared to wildtype tau, while its elongation phase was undetectable. In transfected HEK293T cells, wildtype K18 tau fibrillar seeds did not drive tau aggregation (Strang et al., 2018).

In vitro studies of this variant’s effects on microtubule dynamics showed reduced microtubule elongation compared to wildtype tau (Combs and Gamblin 2012, see also suppl tables). Changes in the lag phase and total microtubule polymerization were also reported, but the statistical significance of the results was unclear.

This variant's PHRED-scaled CADD score (24.6), which integrates diverse information in silico, was 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. Ros R, Thobois S, Streichenberger N, Kopp N, Sánchez MP, Pérez M, Hoenicka J, Avila J, Honnorat J, de Yébenes JG. A new mutation of the tau gene, G303V, in early-onset familial progressive supranuclear palsy. Arch Neurol. 2005 Sep;62(9):1444-50. PubMed.
2. Choumert A, Poisson A, Honnorat J, Le Ber I, Camuzat A, Broussolle E, Thobois S. G303V tau mutation presenting with progressive supranuclear palsy-like features. Mov Disord. 2012 Apr;27(4):581-3. Epub 2011 Nov 22 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. Tubeuf H, Charbonnier C, Soukarieh O, Blavier A, Lefebvre A, Dauchel H, Frebourg T, Gaildrat P, Martins A. Large-scale comparative evaluation of user-friendly tools for predicting variant-induced alterations of splicing regulatory elements. Hum Mutat. 2020 Oct;41(10):1811-1829. Epub 2020 Aug 16 PubMed.
5. 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.
6. 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.

Further Reading

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