Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype Studied: Frontotemporal Dementia, bvFTD, Pick's disease
Position: (GRCh38/hg38):Chr17:46014286 C>T
Position: (GRCh37/hg19):Chr17:44091652 C>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750635
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCC to TTC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 11

Findings

The S320F mutation was the first mutation identified in exon 11 of MAPT. The proband, a man from the Netherlands, developed symptoms at age 38, primarily mild memory problems and spatial disorientation (Rosso et al., 2002). He was originally diagnosed with Alzheimer's disease (AD). He died at age 53 and postmortem examination revealed neuropathology resembling Pick’s disease. His mother also died of dementia at the same age.

The following year, the same group reported an S320F carrier from the Netherlands diagnosed with frontotemporal dementia (FTD; Rosso et al., 2003). This individual appears to be distinct from the man described above since age at onset was 43 years and age at death 54 years. Clinical symptoms included memory loss, apathy, and word-finding difficulty.

A carrier from the U.K. diagnosed with behavioral variant FTD (bvFTD) has also been reported (Rohrer et al., 2010). His age at onset was 51 years.

In an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature, two families, including three presumed carriers, were reported (Moore et al., 2020, suppl tables 5-6). Some or all these carriers may be the same individuals described above. 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 47 years with a mean duration of disease of 10 years. Two of the presumed carriers were diagnosed with bvFTD, and one had dementia not otherwise specified.

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

Neuropathology

Autopsy of the original carrier showed neuropathology resembling Pick’s disease including focal bilateral atrophy of the anterior temporal lobes with only very mild frontal atrophy (Rosso et al., 2002). Severe neuronal loss and gliosis were present in the temporal cortex, cingulate gyrus, entorhinal cortex, and hippocampus. The substantia nigra was not affected.

Tau-positive inclusions characterized by straight and twisted filaments, similar to those described in sporadic Pick's disease, were observed. However, whereas Pick’s disease inclusions are composed of only three-repeat (3R) tau, the insoluble tau fraction from the S320F carrier contained both 3R and 4R tau isoforms. Electron microscopy revealed that the straight tau filaments were similar to those seen in AD and constituted the major species (approximately 80 percent). Both species were hyperphosphorylated.

Biological Effect

Microtubule dynamics
The S320F variant is located in the third repeat (R3) of tau, within the microtubule assembly domain. In vitro assays with isolated proteins have revealed disruption of microtubule assembly, with mutant microtubules having a slower elongation rate (Rosso et al., 2002, Combs and Gamblin, 2012). However, surprisingly, in a cell-based microtubule-binding assay, the mutant protein behaved similarly to wildtype tau (Xia et al., 2019).

Tau Aggregation
Tau aggregation caused by S320F expression has been observed in multiple model systems. For example, in Drosophila, large tau inclusions positive for the AT8 antibody, which recognizes tau phosphorylated at S202, were observed in brain (Bardai et al., 2018). Moreover, mice injected with adeno-associated virus (AAV) carrying MAPT S320F developed moderate deposition of hyperphosphorylated tau with positive staining by MC1 and Alz50 (antibodies that recognize AD tau inclusions), and caspase-cleaved tau at D421 (Koller et al., 2019).

Tau aggregation was also observed in S320F transfected HEK293T cells (Strang et al., 2018). Aggregation was similar using recombinant wildtype fibrils of K18 (a tau fragment containing amyloidogenic hexapeptide motifs) or homotypic mutant fibrils as seeds, and there was no difference between 2N4R and 0N4R tau isoforms. Interestingly, although not as aggregation-prone as other MAPT mutations, S320F was able to induce aggregation without seeding by K18 fibrils.

In vitro experiments showed S320F tau increases the rate of tau nucleation, reducing the aggregation lag phase, and leading to production of short fibrils and oligomers (Combs and Gamblin, 2012; Bardai et al., 2018), which could explain the mutant’s ability to aggregate without the addition of pre-formed fibrils (Strang et al., 2019).

Based on biochemical considerations and electron microscope images, the S320F substitution was predicted to have both local and global conformational effects (Strang et al., 2019). Peptide aggregation experiments using a series of tau fragments have now helped dissect these effects (Chen et al., 2023). S320F appears to destabilize transient nonpolar interactions, stabilizing a local hydrophobic cluster. It also creates new, long-range contacts that expose the amyloidogenic motif ³⁰⁶VQIVYK³¹¹, enhancing self-assembly. This model was supported by computational simulations and experiments using engineered mutations to either enhance or weaken the predicted interactions. 

Other effects
An AD study used S320F tau to examine the interactions between Aβ amyloid and tau pathologies (Koller et al., 2022). In recombinant APP transgenic mice (TgCRND8) injected with AAV-tau constructs, S320F tau appeared to accelerate Aβ plaque deposition, neuroinflammation, and synaptic abnormalities. The effects were observed when the mice were injected neonatally, before they had developed visible amyloid pathology, and not after the mice had developed plaques.

Although S320F removes a potential phosphorylation site in tau, it is unclear if this site is normally or pathologically phosphorylated in vivo (Rosso et al., 2002).

S320F’s PHRED-scaled CADD score, which integrates diverse information in silico, is 33, above the commonly used threshold of 20 for predicting 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.

Research Models

Several research models have been generated by combining S320F with one of two other pathogenic MAPT mutaions: P301L or P301S. S320F and the P301 mutations have synergistic effects on aggregation, with P301 mutations driving elongation, and S320F increasing nucleation. Combining the two results in an aggressive tau strain that fosters amyloid aggregation, including self-aggregation, without requiring exogenous seeding (Strang et al., 2018; Xia et al., 2019).

These double mutation models include cell culture models (e.g., Strang et al., 2018), transgenic mice (e.g., Xia et al., 2022), and models based on the injection of AAV-tau constructs into mouse (e.g., Koller et al., 2019) or rhesus monkey (Beckman et al., 2024) brains, or transduced into organotypic mouse brain slices (e.g., Croft et al., 2019; Feb 2019 news).

To generate models with even more aggressive phenotypes, S320F has been combined with additional pathogenic mutations. For example, human MAPT knockin mice with three MAPT mutations have been created (Morito et al., 2025; May 2025 news). Moreover, these triple mutants have been crossed with APP NL-G-F Knock-in mice which carry three APP mutations. In addition, AAV-tau constructs carrying S320F have been injected into transgenic TgCRND8 mice which carry two APP mutations (Koller et al., 2022).

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References

Mutations Citations

1. MAPT P301L
2. MAPT P301S

News Citations

1. Viral Vectors Trigger Robust Tauopathy in Brain Slices 22 Feb 2019
2. Triple Trouble: New Knock-in Turbocharges Tauopathy 1 May 2025

Research Models Citations

1. APP NL-G-F Knock-in
2. TgCRND8

Paper Citations

1. 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.
2. 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.
3. Xia Y, Prokop S, Bell BM, Gorion KM, Croft CL, Nasif L, Xu G, Riffe CJ, Manaois AN, Strang KH, Quintin SS, Paterno G, Tansey MG, Borchelt DR, Golde TE, Giasson BI. Pathogenic tau recruits wild-type tau into brain inclusions and induces gut degeneration in transgenic SPAM mice. Commun Biol. 2022 May 12;5(1):446. PubMed.
4. Koller EJ, Gonzalez De La Cruz E, Machula T, Ibanez KR, Lin WL, Williams T, Riffe CJ, Ryu D, Strang KH, Liu X, Janus C, Golde TE, Dickson D, Giasson BI, Chakrabarty P. Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy. Hum Mol Genet. 2019 Oct 1;28(19):3255-3269. PubMed.
5. Beckman D, Diniz GB, Ott S, Hobson B, Chaudhari AJ, Muller S, Chu Y, Takano A, Schwarz AJ, Yeh CL, McQuade P, Chakrabarty P, Kanaan NM, Quinton MS, Simen AA, Kordower JH, Morrison JH. Temporal progression of tau pathology and neuroinflammation in a rhesus monkey model of Alzheimer's disease. Alzheimers Dement. 2024 Aug;20(8):5198-5219. Epub 2024 Jun 21 PubMed.
6. Croft CL, Cruz PE, Ryu DH, Ceballos-Diaz C, Strang KH, Woody BM, Lin WL, Deture M, Rodríguez-Lebrón E, Dickson DW, Chakrabarty P, Levites Y, Giasson BI, Golde TE. rAAV-based brain slice culture models of Alzheimer's and Parkinson's disease inclusion pathologies. J Exp Med. 2019 Mar 4;216(3):539-555. Epub 2019 Feb 15 PubMed.
7. Morito T, Qi M, Kamano N, Sasaguri H, Bez S, Foiani M, Duff K, Benner S, Endo T, Hama H, Kurokawa H, Miyawaki A, Mizuma H, Sahara N, Shimojo M, Higuchi M, Saido TC, Watamura N. Human MAPT knockin mouse models of frontotemporal dementia for the neurodegenerative research community. Cell Rep Methods. 2025 Apr 21;5(4):101024. Epub 2025 Apr 11 PubMed.
8. Koller EJ, Ibanez KR, Vo Q, McFarland KN, Gonzalez De La Cruz E, Zobel L, Williams T, Xu G, Ryu D, Patel P, Giasson BI, Prokop S, Chakrabarty P. Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation. Neuropathol Appl Neurobiol. 2022 Feb;48(2):e12779. Epub 2021 Dec 10 PubMed.
9. Rosso SM, van Herpen E, Deelen W, Kamphorst W, Severijnen LA, Willemsen R, Ravid R, Niermeijer MF, Dooijes D, Smith MJ, Goedert M, Heutink P, van Swieten JC. A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick's disease. Ann Neurol. 2002 Mar;51(3):373-6. PubMed.
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11. Rohrer JD, Ridgway GR, Modat M, Ourselin S, Mead S, Fox NC, Rossor MN, Warren JD. Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations. Neuroimage. 2010 Nov 15;53(3):1070-6. Epub 2010 Jan 4 PubMed.
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Further Reading