Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype Studied: rtvFTD, Apraxia of Speech, svPPA
Position: (GRCh38/hg38):Chr17:46014321 C>T
Position: (GRCh37/hg19):Chr17:44091687 C>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCA to TCA
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 11

Findings

This variant has been described in a French family with an unusual and heterogenous clinical phenotype (Deramecourt et al., 2012).

The proband developed a slowly progressing speech disorder starting at the age of 60. Her first symptom was a change in the tone of her voice, which became hypernasal. She developed difficulty swallowing around 10 years later, and was considered to have a syndrome of progressive anarthria (loss of motor ability that enables speech). Up until her death at age 85, her cognition and behavior were unaffected.

The proband's two sons developed a form of frontotemporal dementia (FTD) characterized by behavioral and semantic impairments. At 48 and 50 years of age they developed increasing forgetfulness, progressive prosopagnosia ("face blindness"), specific semantic impairments, and behavioral changes such as self-neglect and compulsive eating. One of the brothers reportedly lost the ability to "differentiate good wines from bad ones." MRI in both brothers showed bilateral anterior temporal lobe atrophy, consistent with a temporal variant of frontotemporal lobar degneration. In a subsequent study, the condition was described as right temporal variant FTD (Villa et al., 2024).

All three affected family members were mutation carriers. DNA was not available from additional family members to confirm segregation with disease.

In an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature (including the Deramecourt et al., 2012 study described above), one family  with this mutation, including three affected individuals, was reported (Moore et al., 2020, suppl tables 5-6). Two of the carriers were classified as having the semantic variant of primary progressive aphasia (svPPA) and one as having dementia not otherwise specified.

This variant was absent from the gnomAD variant database (v4.1.0, Apr 2024).

Neuropathology

Neuropathological examination of the proband showed atrophy in primary motor and premotor cortices, along with spongiosis, gliosis, and neuronal loss. Neuronal tau-positive lesions were present, especially in the dentate gyrus. The lesions contained both 3-repeat (3R) and 4-repeat (4R) tau isoforms and resembled Pick bodies. Some neurofibrillary tangles were also observed. Immunohistochemistry for TDP-43, prion protein, and α-synuclein were negative (Deramecourt et al., 2012).

Biological Effect

This mutation affects a highly conserved amino acid in the PGGG repeat of the third microtubule binding domain of tau protein. The mutation appears to decrease tau’s capacity to bind microtubules (Deramecourt et al., 2012). The evidence is indirect, however: in transfected HEK cells, the ratio of tau in the Triton X100-soluble cytosolic fraction to tau in the insoluble (microtubule-containing) fraction was lower than in cells transfected with wildtype tau.

In most cases, this mutation does not appear to fuel tau aggregation unlike P301S, the analogous mutation in the PGGG motif of the second microtubule binding domain. For example, P332S did not influence the propensity of tau to aggregate in human embryonic kidney (HEK) cells with or without preformed seeds composed of the wildtype K18 tau peptide (Strang et al., 2018).

A subsequent study, however, showed that three PGGG mutants, including P332S, have different effects on tau aggregation depending on the molecule used to induce aggregation (Ingham et al., 2022). Consistent with Strang and coworkers’ study, in the presence of most aggregation inducers, P332S tau had similar, or even weaker, effects on aggregation than wildtype tau. However, aggregation induced by polyphosphate P100, yielded longer tau filaments than wildtype tau, as assessed by electron microscopy, although the number of mutant filaments was lower. Moreover, the use of non-coding RNAs (sRNA and lRNA) as inducers resulted in increased numbers of filaments compared to those formed with wildtype tau.

P332S’s PHRED-scaled CADD score, which integrates diverse information in silico, is 29.5, well above the commonly used threshold of 20 for predicting deleteriousness (CADD v1.7, Oct 2025).

Pathogenicity

Frontotemporal Dementia Spectrum : Likely 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

Mutations Citations

1. MAPT P301S

Paper Citations

1. Deramecourt V, Lebert F, Maurage CA, Fernandez-Gomez FJ, Dujardin S, Colin M, Sergeant N, Buée-Scherrer V, Clot F, Ber IL, Brice A, Pasquier F, Buée L. Clinical, neuropathological, and biochemical characterization of the novel tau mutation P332S. J Alzheimers Dis. 2012;31(4):741-9. 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. 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.
5. Ingham DJ, Hillyer KM, McGuire MJ, Gamblin TC. In vitro Tau Aggregation Inducer Molecules Influence the Effects of MAPT Mutations on Aggregation Dynamics. Biochemistry. 2022 Jul 5;61(13):1243-1259. Epub 2022 Jun 22 PubMed.

Further Reading

No Available Further Reading