Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP3
Clinical Phenotype Studied: Corticobasal Syndrome, bvFTD, Globular Glial Tauopathy
Position: (GRCh38/hg38):Chr17:46010388 C>A
Position: (GRCh37/hg19):Chr17:44087754 C>A
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63751438
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Missense
Codon Change: CCG to ACG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This was the third mutation discovered at the 301 codon in MAPT. It was identified in a 57-year-old man with a two-year history of cognitive decline, gait disturbances, behavioral changes, apathy, speech difficulties, and falls. MRI showed mild global atrophy that was more prominent in the frontal and temporal lobes. Four family members had similar symptoms, but genetic analysis was not possible and segregation could not be assessed (Lladó et al., 2007).

Subsequently the P301T mutation was found in two additional families from the Navarra region of northern Spain (Erro et al., 2019). The clinical presentations of afflicted individuals varied, but neuropathological findings support a diagnosis of familial globular glial tauopathy (GGT).

Two members of the first family, a mother and son, received clinical evaluations. The mother was diagnosed with corticobasal syndrome at age 68, and she died four years later. Imaging studies prior to death revealed atrophy of the left parietal and temporal cortices. Her son started showing gait disturbances at age 45, and after neurological examination, he received a diagnosis of primary lateral sclerosis syndrome. As his disease progressed, he exhibited speech difficulties, cognitive decline, and abnormal behavior. MRI revealed atrophy of frontotemporal cortex, left hippocampus, and mesencephalon, as well as white-matter lesions. He died at age 49. The son was found to be heterozygous for the MAPT P301T mutation; genetic data were not available from the mother. Additionally, the father of the female patient was reported to have died at age 53, after experiencing rapid cognitive decline.

Three siblings from the second family were clinically evaluated and genotyped. Two brothers were diagnosed with corticobasal syndrome in their 40s, while their sister was diagnosed with frontotemporal dementia at age 55. The average disease duration among these patients was five to six years. MRI revealed frontotemporal atrophy in one brother, posterior parietal atrophy and white-matter involvement in the other brother, and white-matter lesions in the sister. All three siblings were heterozygous for the MAPT P301T mutation. Family history included several other relatives who reportedly suffered from neurological deficits, including the mother of the three siblings, who died at age 54 after a period of rapid cognitive decline.

In an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature, one family, including five 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 49.8 years and the mean age at death was 52.3 years. Two of the presumed carriers were diagnosed with bvFTD, and three had dementia not otherwise specified. Of note, the family reported in this study may be the same as one of the families described above.

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

Neuropathology

Neuropathological data are available from four of the five patients in the Spanish case series originally reported by Erro and colleagues (Erro et al., 2019). The most striking finding was the presence of globular deposits composed of four-repeat (4R) tau in astrocytes and oligodendrocytes in all of the cases examined. Other findings include neuron loss in frontal cortex, substantia nigra, and spinal cord; spongiosis and astrogliosis in cortex and subcortical regions; neurofibrillary tangles; and demyelination of the corticospinal tracts.

Further analyses of tissues from the frontal cortex and the underlying white matter of these carriers revealed increased expression of astrocytic mRNAs and proteins, decreased expression of glutamate (EAAT2) and glucose (SLC2A1) transporters, disruption of the expression of some mitochondrial proteins in frontal cortex, and decreased expression of oligodendrocyte markers in white matter (Ferrer et al., 2020). In addition, the phosphorylation patterns of multiple neuronal proteins, in addition to tau, were disrupted.

Biological Effect

P301T is in the highly conserved PGGG repeat of the second repeat domain within tau’s microtubule-binding domain. It affects only 4-repeat (4R) tau isoforms because it is in exon 10 which is spliced out of 3-repeat (3R) isoforms. When the mutant protein was expressed in HEK293T cells, tau binding to microtubules was reduced compared to cells expressing the wildtype protein (Xia et al., 2019).

The P301T substitution also promotes the assembly of tau filaments. When the mutant protein was expressed in HEK293T cells, for example, recombinant fibrils of the aggregation-seeding peptide K18 induced aggregation, whether the K18 fibrils carried the mutation or not (Strang et al., 2017). The effect was observed with either 2N4R or 0N4R tau isoforms. In addition, when heparin was used to induce aggregation of recombinant tau constructs in vitro, mutant tau formed intermediate oligomers more readily than wildtype tau (Maeda et al., 2018). In vivo studies also indicate P301T fuels tau aggregation. For example, inoculation of detergent-insoluble fractions isolated from the frontal cortex and white matter of affected P301T carriers into the brains of wildtype mice resulted in seeding and spreading of tau aggregates (Ferrer et al., 2020),

A cryo-EM study of tau filaments isolated from a P301T carrier revealed a two-layered core fold comprised of microtubule binding repeats R2-R4 as the predominant structure (Schweighauser et al., 2025; March 2025 news). These structures were woven into fibrils made of single protofilaments. Interestingly, the P301T structure differed substantially from the structures of filaments isolated from sporadic cases of GGT. It also differed from the predominant structure formed by tau isolated from P301L carriers, although a few P301T filaments adopted a P301L-like shape with the middle of the R2 domain bulging out.

Multiple studies have examined the structural role of P301. Tau hexapeptides 275VQIINK280 and 306VQIVYK311 are masked in wildtype tau molecules, and their exposure fuels tau seeding and aggregation (e.g., Falcon et al., 2015; Mirbaha et al., 2018; MacDonald et al., 2019). A few amino acids in-between, including P301, seem to normally inhibit this exposure (e.g., Strang et al., 2018). The 306VQIVYK311 sequence in particular appears to form a metastable compact structure with the upstream 301PGGG304 repeat which modulates tau’s propensity to aggregate (Chen et al., 2019).

Also of note, in a cell-based minigene splicing assay, P301T increased exon 10 skipping (Tubeuf et al., 2020), which is expected to result in increased 3R over 4R tau isoforms.

P301T’s PHRED-scaled CADD score (27.7), 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*

*Clinical phenotypes varied between carriers.

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

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

1. Filling in the Family Tree: AD, CTE Folds Spotted in Other Tauopathies 27 Mar 2025

Mutations Citations

1. MAPT P301L

Paper Citations

1. Lladó A, Ezquerra M, Sánchez-Valle R, Rami L, Tolosa E, Molinuevo JL. A novel MAPT mutation (P301T) associated with familial frontotemporal dementia. Eur J Neurol. 2007 Aug;14(8):e9-10. PubMed.
2. Erro ME, Zelaya MV, Mendioroz M, Larumbe R, Ortega-Cubero S, Lanciego JL, Lladó A, Cabada T, Tuñón T, García-Bragado F, Luquin MR, Pastor P, Ferrer I. Globular glial tauopathy caused by MAPT P301T mutation: clinical and neuropathological findings. J Neurol. 2019 Oct;266(10):2396-2405. Epub 2019 Jun 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. Ferrer I, Andrés-Benito P, Zelaya MV, Aguirre ME, Carmona M, Ausín K, Lachén-Montes M, Fernández-Irigoyen J, Santamaría E, Del Rio JA. Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy. Acta Neuropathol. 2020 Apr;139(4):735-771. Epub 2020 Jan 6 PubMed.
5. 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.
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.
7. Maeda S, Sato Y, Takashima A. Frontotemporal dementia with Parkinsonism linked to chromosome-17 mutations enhance tau oligomer formation. Neurobiol Aging. 2018 Sep;69:26-32. Epub 2018 May 7 PubMed.
8. Schweighauser M, Shi Y, Murzin AG, Garringer HJ, Vidal R, Murrell JR, Erro ME, Seelaar H, Ferrer I, van Swieten JC, Ghetti B, Scheres SH, Goedert M. Distinct tau filament folds in human MAPT mutants P301L and P301T. Nat Struct Mol Biol. 2025 Aug;32(8):1470-1478. Epub 2025 May 29 PubMed.
9. Falcon B, Cavallini A, Angers R, Glover S, Murray TK, Barnham L, Jackson S, O'Neill MJ, Isaacs AM, Hutton ML, Szekeres PG, Goedert M, Bose S. Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem. 2015 Jan 9;290(2):1049-65. Epub 2014 Nov 18 PubMed.
10. Mirbaha H, Chen D, Morazova OA, Ruff KM, Sharma AM, Liu X, Goodarzi M, Pappu RV, Colby DW, Mirzaei H, Joachimiak LA, Diamond MI. Inert and seed-competent tau monomers suggest structural origins of aggregation. Elife. 2018 Jul 10;7 PubMed.
11. Macdonald JA, Bronner IF, Drynan L, Fan J, Curry A, Fraser G, Lavenir I, Goedert M. Assembly of transgenic human P301S Tau is necessary for neurodegeneration in murine spinal cord. Acta Neuropathol Commun. 2019 Mar 18;7(1):44. PubMed.
12. Chen D, Drombosky KW, Hou Z, Sari L, Kashmer OM, Ryder BD, Perez VA, Woodard DR, Lin MM, Diamond MI, Joachimiak LA. Tau local structure shields an amyloid-forming motif and controls aggregation propensity. Nat Commun. 2019 Jun 7;10(1):2493. PubMed.
13. 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.

Further Reading