Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP3
Clinical Phenotype Studied: bvFTD
Position: (GRCh38/hg38):Chr17:46018686 T>A
Position: (GRCh37/hg19):Chr17:44096052 T>A
Transcript: NM_005910; ENST00000351559
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCC to ACC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This mutation has been reported in two family members affected by the behavioral variant of frontotemporal dementia (bvFTD) (Momeni et al., 2010). The proband developed behavioral symptoms at age 29, including disinhibition, theft, and stereotyped behavior. She was initially diagnosed with schizophrenia, but her diagnosis was later corrected to bvFTD. The proband’s father was also a mutation carrier. He was diagnosed with schizophrenia at the age of 27 following changes in personality and behavior including aggression and apathy. He died at age 42; postmortem examination revealed neuropathology consistent with bvFTD (see below). The mutation was absent in three unaffected family members (the proband’s mother and two paternal siblings), suggesting segregation with disease.

Like the proband in this family, an unrelated carrier was also initially diagnosed with schizophrenia (Kahn et al., 2012). She was a woman in the United States who presented with delusions, eating abnormalities, disorganized behavior, lack of insight, disinhibition, and stereotypical motor behaviors at age 35. As noted below, brain MRI imaging revealed atrophy consistent with FTD.

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

Neuropathology

Autopsy revealed frontotemporal lobar degeneration and hippocampal atrophy (Momeni et al., 2010). Some spongiosis was noted in the cortex. Abundant tau pathology, including mature neurofibrillary tangles was observed, especially in the cortex, hippocampus, and substantia nigra. Pretangles were more widespread. Tau-positive threads and grains were also noted, as were Pick body-like amorphous globular neurofibrillary inclusions. Beta-amyloid pathology was largely absent.

Brain MRI of another carrier showed severe bilateral frontal orbital and insular atrophy (Kahn et al., 2012).

Biological Effect

The most dramatic biological effect associated with S356T is its ability to fuel the aggregation of tau containing three microtubule-binding repeats (3R tau) (Xia et al., 2023). Earlier observations in human embryonic kidney cells (HEK293T) expressing the 4R tau isoform 0N4R revealed a modest effect of the mutation, increasing aggregation only mildly, either in the presence or absence of K18 peptides—tau fragments that can seed aggregation (Xia et al., 2019). The effect remained modest, even when S356T was expressed together with the aggregation-prone P301L mutation.

In contrast, cells expressing mutant 0N3R tau developed numerous, large thioflavin-positive aggregates (Xia et al., 2023). These aggregates formed only when the cells were treated with aggregation-prone K19 seeds, suggesting prion-like seeding. The phosphorylation patterns of soluble and insoluble tau fractions differed, with T205 phosphorylated in both fractions, as assessed with 7F2 antibodies, and T231 phosphorylated only in the soluble fraction, as assessed with AT180 antibodies.

As noted by the authors, the replacement of a serine with a threonine is a relatively minor change, but the additional methyl group could boost nonpolar interactions that accelerate tau filament formation (Xia et al., 2023). The mutation is near the R4 PGGG motif, which is thought to form part of tau filament cores. Moreover, it has been suggested that the stretch of amino acids between positions 353 and 368 acts as a regulator of the formation of fibrous tau structures like those found in Alzheimer’s disease (Shimonaka et al., 2020). Phosphorylation changes may also play a role in S356T’s effects on tau aggregation (Xia et al., 2023). In addition to those described above, S356 itself is a phosphorylation site that has been reported in tau filaments from AD brains. Moreover, as further noted by Xia and colleagues, S356 is located within the KXGS motif, close to the K353 acetylation site which has been reported to reduce tau aggregation. S356T may allosterically hinder K353 acetylation.

The effects of S356T on microtubule binding also appear to depend on the tau isoform studied. S356 resides in the 4R region of tau’s microtubule-binding domain so it is not surprising that S356T affects tau’s interactions with microtubules. However, while 0N4R mutant tau bound less strongly to microtubules than wildtype 0N4R (Xia et al., 2019), 0N3R bound more strongly than its wildtype counterpart  (Xia et al., 2023). Experiments were done in transfected HEK293T cells treated with paclitaxel to stabilize microtubule assembly and enable isolation of proteins that associate with microtubules after high-speed centrifugation.

This variant's PHRED-scaled CADD score (27.8), 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.

Research Models

To facilitate recombinant protein studies, a plasmids library has been developed containing S356T mutant full-length tau and the K18 tau fragment—the four-repeat tau microtubule-binding region used for seeding aggregation (Karikari et al., 2020). Cysteine-modified variants were also generated.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Mutations Citations

1. MAPT P301L

Paper Citations

1. Karikari TK, Keeling S, Hill E, Lantero Rodrı Guez J, Nagel DA, Becker B, Höglund K, Zetterberg H, Blennow K, Hill EJ, Moffat KG. Extensive Plasmid Library to Prepare Tau Protein Variants and Study Their Functional Biochemistry. ACS Chem Neurosci. 2020 Oct 7;11(19):3117-3129. Epub 2020 Sep 16 PubMed.
2. Momeni P, Wickremaratchi MM, Bell J, Arnold R, Beer R, Hardy J, Revesz T, Neal JW, Morris HR. Familial early onset frontotemporal dementia caused by a novel S356T MAPT mutation, initially diagnosed as schizophrenia. Clin Neurol Neurosurg. 2010 Dec;112(10):917-20. PubMed.
3. Khan BK, Woolley JD, Chao S, See T, Karydas AM, Miller BL, Rankin KP. Schizophrenia or neurodegenerative disease prodrome? Outcome of a first psychotic episode in a 35-year-old woman. Psychosomatics. 2012;53(3):280-4. Epub 2012 Jan 28 PubMed.
4. 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.
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. 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.

Further Reading

No Available Further Reading