Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Uncertain Significance
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PP3, BS1, BS2
Clinical Phenotype Studied: bvFTD, Parkinsonism
Position: (GRCh38/hg38):Chr17:46018675 C>T
Position: (GRCh37/hg19):Chr17:44096041 C>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750425
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCG to TTG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This mutation may have reduced penetrance—it has been identified in individuals with tauopathy disorders, as well as in cognitively healthy family members.

It was first reported in homozygous form in an a consanguineous English family referred to as the Yorkshire kindred. It was found in a pair of siblings with aggressive early onset hereditary tauopathy, who presented with acute respiratory failure. The parents were unaffected (at least at the time of assessment) despite carrying the S352L mutation in heterozygous form (Nicholl et al., 2003).

The variant was subsequently reported in a 58-year-old heterozygote from the Amsterdam Dementia Cohort diagnosed with the right temporal variant of FTD (Ulugut Erkoyun et al., 2021; Ulugut et al., 2021). Before autopsy, his diagnosis was FTD with atypical parkinsonism. He presented with behavioral changes, depression, memory deficits, and developed prosopagnosia and atypical parkinsonism. His mother had psychiatric symptoms and his maternal uncle developed dementia at the age of 85.

This variant was reported in the gnomAD public variant database at a global frequency of 0.0000025, including four heterozygotes of non-Finnish European ancestry (gnomAD v4.1.1, Apr 2024).

Neuropathology

Extensive tau neuropathology was observed in the three affected carriers (Nicholl et al., 2003; Ulugut Erkoyun et al., 2021). In the English siblings, tauopathy was most prominent in the gray matter of the hippocampus, thalamus, pons, and medulla, with some tauopathy seen in the white matter of the pons and medulla. Of note, no tau lesions were observed in cortical areas. Evidence of hypoxic brain damage was reported. In the Dutch carrier, mesial temporal atrophy was observed, with the right side being more severely affected (Ulugut Erkoyun et al., 2021). Tauopathy included both three-repeat (3R) and four-repeat (4R) tau. Phospho-tau (AT8 antibody) was observed across all layers in anterior cingulate cortex. Before autopsy, SPECT-PET imaging of this individual’s brain revealed right temporal hypo-perfusion (Ulugut et al., 2021).

Biological Effect

S352L appears to alter the binding of tau to microtubules and may also affect tau aggregation, although results have been mixed. In their original report, Nicholl and colleagues reported recombinant S352L tau exhibited reduced microtubule assembly and lower affinity for microtubule binding (Nicholl et al., 2003). Consistent with these findings, a subsequent in vitro study found that 2N4R mutant tau induced microtubule elongation at a slower rate and the lag time for microtubule polymerization was increased (Combs and Gamblin, 2012). Moreover, in an assay using human embryonic kidney 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 0N3R tau isoforms (Xia et al., 2023).

The effects of S352L on tau aggregation vary between experimental systems. In a Drosophila model expressing human 0N4R tau in glial cells, the mutant protein induced larger tau inclusions (AT8-positive) in glia than wildtype tau (Bardai et al., 2018). In the same study, the authors found that, in assays with isolated proteins, 0N4R mutant tau generated a similar number of tau filaments as wildtype tau, but the mutant filaments were substantially longer. Moreover, in the original study describing this mutation, recombinant mutant tau showed accelerated filament formation in vitro (Nicholl et al., 2003), and in another in vitro study, enhanced polymerization of 2N4R tau was observed, as assessed by thioflavin S fluorescence and laser light scattering (Combs and Gamblin, 2012). However, in cultured cells, neither 0N4R mutant tau (Xia et al., 2019) nor 0N3R mutant tau (Xia et al., 2023) induced 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.

The molecular underpinnings of these effects remain unclear, but one group suggested S352L may enhance β-strand formation around the ³⁵⁰VQLKI sequence, adding another amyloidogenic sequence to tau’s two other amyloidogenic motifs ²⁷⁵VQIINK and ³⁰⁶VQIVYK (Combs and Gamblin, 2012). This may help stabilize longer tau filaments.

Unlike several known pathogenic MAPT mutations, no changes in number of cleaved caspase positive cells, interaction with actin, autophagy, or activation of the unfolded protein response were observed in flies expressing the mutant protein in neuronal cells (Bardai et al., 2018).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was 33, well above the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Uncertain Significance*

*This variant may have reduced penetrance, a condition outside the scope of the ACMG-AMP guidelines.

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

Paper Citations

1. Nicholl DJ, Greenstone MA, Clarke CE, Rizzu P, Crooks D, Crowe A, Trojanowski JQ, Lee VM, Heutink P. An English kindred with a novel recessive tauopathy and respiratory failure. Ann Neurol. 2003 Nov;54(5):682-6. PubMed.
2. Ulugut Erkoyun H, van der Lee SJ, Nijmeijer B, van Spaendonk R, Nelissen A, Scarioni M, Dijkstra A, Samancı B, Gürvit H, Yıldırım Z, Tepgeç F, Bilgic B, Barkhof F, Rozemuller A, van der Flier WM, Scheltens P, Cohn-Hokke P, Pijnenburg Y. The Right Temporal Variant of Frontotemporal Dementia Is Not Genetically Sporadic: A Case Series. J Alzheimers Dis. 2021;79(3):1195-1201. PubMed.
3. Ulugut H, Dijkstra AA, Scarioni M, Netherlands Brain Bank, Barkhof F, Scheltens P, Rozemuller AJ, Pijnenburg YA. Right temporal variant frontotemporal dementia is pathologically heterogeneous: a case-series and a systematic review. Acta Neuropathol Commun. 2021 Aug 3;9(1):131. PubMed.
4. Combs B, Gamblin TC. FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions. Biochemistry. 2012 Oct 30;51(43):8597-607. Epub 2012 Oct 18 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. 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.
7. Bardai FH, Wang L, Mutreja Y, Yenjerla M, Gamblin TC, Feany MB. A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo. J Neurosci. 2018 Jan 3;38(1):108-119. Epub 2017 Nov 14 PubMed.

Further Reading

No Available Further Reading