Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype Studied: Corticobasal Syndrome, Progressive Supranuclear Palsy, PPA, Parkinsonism
Position: (GRCh38/hg38):Chr17:46018708 T>C
Position: (GRCh37/hg19):Chr17:44096074 T>C
Transcript: NM_005910; ENST00000351559
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTC to GCC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This variant was identified in an Italian man diagnosed with progressive supranuclear palsy (PSP; Rossi et al., 2014). At age 53, he developed oculomotor dysfunction, followed by postural instability with falls, mild bradykinesia, and increased deep tendon reflexes. One year later, he had speech and writing impairments, as well as autonomic complications. Slight parkinsonism, supranuclear gaze palsy, speech abnormalities, and mild impulsivity were detected three years after onset.

The proband’s father developed atypical parkinsonism at age 65, and like his son, had postural instability with falls, bradykinesia, and cognitive impairment. He died two years after onset. In addition, the proband’s paternal grandfather developed dementia at age 56.

Genetic analysis revealed the proband carried V363A. Analyses of his MAPT, GRN, and C9ORF72 genes revealed no other candidate pathogenic mutations. He was homozygous for the H1 haplotype of MAPT. The proband’s mother did not carry the mutation, nor did 100 healthy subjects and 300 non-FTD neurological patients.

Of note, a subsequent study described the proband as having PSP with a mixed diagnosis of corticobasal syndrome (CBS), progressive primary aphasia (PPA), and left-sided parkinsonism (Villa et al., 2024). In addition, in an international, retrospective cohort study, two individuals who appear to correspond to members of this family were described as having Parkinson’s disease, and another member as having dementia not otherwise specified (Moore et al., 2020 suppl). The mean age of disease onset was reported as 58 years and the mean duration of disease as 2.0 years.

This variant was absent from the variant database gnomAD (v.4.1.0, Aug 2025).

Neuropathology
Neuropathological data are unavailable, but a brain MRI scan of the proband showed midbrain atrophy (Rossi et al., 2014). In addition, he had bilateral dopaminergic denervation, as revealed by dopamine transporter (DAT) imaging. Abnormalities in left frontotemporal theta waves were observed in an electroencephalogram.

Biological Effect
The valine at position 363, a highly conserved amino acid, resides in the fourth repeat of tau’s microtubule assembly domain, immediately adjacent to the PGGG sequence, a motif involved in microtubule binding and aggregation. In a cell-free assay, V363I tau reduced microtubule assembly compared to wildtype tau, slowing polymerization kinetics and leading to the formation of few, very long tubulin polymers (Rossi et al., 2014). Moreover, in an assay using human embryonic kidney (HEK293T) cells in the presence of the microtubule-stabilizing agent paclitaxel, binding of tau to microtubules was reduced in cells expressing the 0N4R mutant isoform compared to cells expressing wildtype 0N4R (Xia et al., 2019). However, no differences in binding were detected in cells expressing the 0N3R isoforms (Xia et al., 2023).

Several studies have indicated V363A has little effect on tau aggregation, although V363 is within a stretch of amino acids that has been suggested to modify tau fibril formation (Shimonaka et al., 2020). In transgenic worms expressing the human 2N4R tau isoform in neurons, for example, the solubility of the mutant protein in detergent or formic acid was similar to that of wildtype tau, indicating the mutant protein was not enriched in cell membranes or insoluble assemblies (Morelli et al., 2018). Also, tau phosphorylation levels of T231 (AT180) and S202/T205 (AT8) were similar in worms expressing either the mutant or wildtype protein. Moreover, in cultured cells, neither 0N4R mutant tau (Xia et al., 2019) nor 0N3R mutant tau (XIa et al., 2023) induce aggregation in a manner that was statistically significant different from wildtype tau, either in the presence or absence of K18 or K19, tau fragments that seed aggregation .

Three studies using different cell-free assays also indicated little or no effect of the mutation on aggregation. In one study, mutant tau was observed to polymerize relatively quickly, but slow down rapidly, resulting in mostly oligomers and very rare short fibrils intermingled with amorphous material (Rossi et al., 2014). Moreover, light scattering analysis and Congo red staining showed V363A behaving similarly to wildtype tau, with very low levels of putative β-sheet structure. Another in vitro study reported monomeric mutant tau in solution had an intrinsically disordered shape like that of wildtype tau (De Luigi et al., 2022). Moreover, the kinetics of β-sheet structure and fibril formation were very slow, resulting in intermediate aggregation species that were shorter and less abundant than the large aggregates formed by P301L, a pathogenic tau mutant. Interestingly, in a study that used biosensor cells to define the roles of individual tau amino acids in tau aggregation, V363A tau did not appreciably affect monomer incorporation in cells seeded with fibrils from patients with a range of tauopathies, including PSP, corticobasal degeneration, Alzheimer’s disease, or chronic traumatic encephalopathy (Vaquer-Alicea et al., 2025).

The effects of V363A on other processes have also been studied. In transgenic worms, pharyngeal pumping, but not body bending, was reduced, suggesting some degree of specificity in the neuronal types affected by the mutation (Morelli et al., 2018). The authors also found enhanced sensitivity to the acetylcholine receptor agonist levamisole, but not to the acetylcholinesterase inhibitor aldicarb, suggesting a presynaptic defect. A modest effect of the mutation on the viability of human neuroblastoma SH-SY5Y cells was reported (De Luigi et al., 2022), with no significant effect on the survival of transgenic worms (Morelli et al., 2018).

This variant’s PHRED-scaled CADD score was 26.6, above the commonly used threshold to assess deleteriousness of 20 (CADD v1.7, Aug 2025).

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

Mutations Citations

1. MAPT P301L

Paper Citations

1. Rossi G, Bastone A, Piccoli E, Morbin M, Mazzoleni G, Fugnanesi V, Beeg M, Del Favero E, Cantù L, Motta S, Salsano E, Pareyson D, Erbetta A, Elia AE, Del Sorbo F, Silani V, Morelli C, Salmona M, Tagliavini F. Different mutations at V363 MAPT codon are associated with atypical clinical phenotypes and show unusual structural and functional features. Neurobiol Aging. 2014 Feb;35(2):408-17. Epub 2013 Sep 7 PubMed.
2. Villa C, Pellencin E, Romeo A, Giaccone G, Rossi G, Prioni S, Caroppo P. Dissecting the Clinical Heterogeneity and Genotype-Phenotype Correlations of MAPT Mutations: A Systematic Review. Front Biosci (Landmark Ed). 2024 Jan 16;29(1):12. 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. 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.
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. Shimonaka S, Matsumoto SE, Elahi M, Ishiguro K, Hasegawa M, Hattori N, Motoi Y. Asparagine residue 368 is involved in Alzheimer's disease tau strain-specific aggregation. J Biol Chem. 2020 Oct 9;295(41):13996-14014. Epub 2020 Aug 5 PubMed.
7. Morelli F, Romeo M, Barzago MM, Bolis M, Mattioni D, Rossi G, Tagliavini F, Bastone A, Salmona M, Diomede L. V363I and V363A mutated tau affect aggregation and neuronal dysfunction differently in C. elegans. Neurobiol Dis. 2018 Sep;117:226-234. Epub 2018 Jun 22 PubMed.
8. De Luigi A, Colombo L, Russo L, Ricci C, Bastone A, Cimini S, Tagliavini F, Rossi G, Cantù L, Del Favero E, Salmona M. Biochemical and biophysical features of disease-associated tau mutants V363A and V363I. Biochim Biophys Acta Proteins Proteom. 2022 Mar 1;1870(3):140755. Epub 2022 Jan 5 PubMed.
9. Vaquer-Alicea J, Manon VA, Bommareddy V, Kunach P, Gupta A, Monistrol J, Perez VA, Tran HT, Saez-Calveras N, Du S, Batra S, Stoddard D, White CL 3rd, Joachimiak LA, Shahmoradian SH, Diamond MI. Functional classification of tauopathy strains reveals the role of protofilament core residues. Sci Adv. 2025 Jan 24;11(4):eadp5978. Epub 2025 Jan 22 PubMed.

Further Reading

No Available Further Reading