Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP3
Clinical Phenotype Studied: nfvPPA, bvFTD, Argyrophilic Grain Disease
Position: (GRCh38/hg38):Chr17:46010401 G>T
Position: (GRCh37/hg19):Chr17:44087767 G>T
Transcript: NM_005910; ENST00000351559
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Missense
Codon Change: AGT to ATT
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This mutation was first identified in a Hungarian individual who, at the age of 39, developed behavior and personality changes  (Kovacs et al., 2008). He rapidly developed progressive speech and movement disorders with cognitive impairment, depression, and anxiety. He died at age 41 with symmetric parkinsonism, vertical gaze palsy, bulbar symptoms, and severe dementia. The patient's clinical presentation and neuropathology are were very similar to those seen inconsistent with the sporadic tauopathy argyrophilic grain disease (AGD), a tauopathy tightly tied to aging (Langerscheidt et al., 2024). It has been suggested that AGD might be included in the differential diagnosis of patients presenting with the behavioral variant of frontal temporal dementia (bvFTD; Gil et al., 2019), and indeed, a subsequent report classified the disorder as bvFTD (Karch et al., 2019). 

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). 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 41 years with a mean duration of disease of 3.5 years. Two of the presumed carriers were diagnosed with bvFTD, and one with the non-fluent variant of primary progressive aphasia (nfvPPA).

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

Neuropathology
Neuropathological analysis of brain tissue from the original proband showed features reminiscent of AGD. extensive Extensive neuronal loss and astrogliosis were observed in the medial temporal cortex, hippocampus, and amygdala, which was particularly enriched in ballooned neurons. Classical neurofibrillary tangles, Pick bodies, and neuritic plaques were not observed. There was evidence of diffuse cytoplasmic tau staining in neurons, thorn-shaped inclusions in astrocytes, and coiled bodies in oligodendrocytes, as well as argyrophilic grains. The tau-positive structures were composed only of 4-repeat (4R) tau isoforms that formed straight filaments (Kovacs et al., 2008).

In a 37-year-old carrier with behavioral symptoms and nonfluent aphasia, tau aggregates with an apparent Alzheimer’s-like structure were identified, as assessed by 18F-flortaucipir brain scans (Tsai et al., 2019).  The ¹⁸F-flortaucipir signal was observed in bilateral frontal, temporal, parietal lobes and the corresponding white matter.

Biological Effect
This mutation, located 2 base pairs before the exon 10/intron 10 splice site, affects exon 10 splicing, causing an overproduction of 4-repeat (4R) tau isoforms, as assessed by PCR analysis of RNA extracted from the proband's frontal cortex (Kovacs et al., 2008). The effect has also been observed in neurons and astrocytes derived from mutant induced pluripotent stem cells (iPSCs; Bowles et al., 2024). An increase in 4R transcripts was detected as early as four weeks after iPSCs were differentiated into neurons. Interestingly, the percentage of mutant 4R transcripts in astrocytes (20 to 30 percent) was greater than in neurons (5 to 15 percent). Also of note, the alteration varied between donor lines suggesting genetic background may influence the pathogenicity of this mutation.

Studies using iPSC-derived neurons also showed S305I is associated with increased firing rates as early as 3 weeks after differentiation and, at 6 weeks, upregulation of exocytosis- and vesicle transport-related pathways was observed (Bowles et al., 2024). Moreover, synaptic markers were increased in synaptosome preparations compared to those of isogenic controls. These preparations also showed increased levels of total tau and phospho-tau S396.

Transcriptomic analysis of mutant iPSCs also revealed a progressive upregulation of mitochondria-related pathways and of ribosomal and endoplasmic reticulum stress pathways (Bowles et al., 2024). In addition, downregulation of the expression of proteins involved in extracellular matrix organization and changes in RNA metabolism was reported.

Interestingly, while ribosomal and translation-regulation pathways were upregulated in neurons, they were downregulated in astrocytes (Bowles et al., 2024). Also of note, non-mitochondrial respiration was increased, an effect that the authors suggested may be tied to increased inflammation and oxidative stress. Indeed, mutant astrocytes had increased baseline levels of the inflammatory chemokine CXCL5.

The effects of S305I on tau aggregation are unknown. Interestingly, however, in vitro studies suggest that replacing S305 with a lysine can reduce the seeding activity of tau peptides by keeping tau’s amyloidogenic PHF6 sequence buried (Apr 2024 news; Longhini et al., 2024). Moreover, S305 is a phosphorylation site that appears to affect tau seeding and aggregation. The S305E phosphomimetic mutation inhibited both of these processes (Strang et al., 2019).

This variant's PHRED-scaled CADD score (32), which integrates diverse information in silico, was well 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

As described above, several iPSC lines carrying the S305I variant have been generated. Cells from a symptomatic female carrier were initially reported (Nimsanor et al., 2016). Subsequently, a collection of iPSC lines, including original S305I heterozygote clones, isogenic corrected lines, and lines edited to be homozygous for S305I, have been generated (Karch et al., 2019; Oct 2019 news; Bowles et al., 2024).

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References

News Citations

1. Introducing: iPSC Collection from Tauopathy Patients 23 Oct 2019
2. Tau Toggling Peptides: One Seeds Fibrils; the Other Dismantles Them 19 Apr 2024

Paper Citations

1. Nimsanor N, Jørring I, Rasmussen MA, Clausen C, Mau-Holzmann UA, Kitiyanant N, Nielsen JE, Nielsen TT, Hyttel P, Holst B, Schmid B. Induced pluripotent stem cells (iPSCs) derived from a symptomatic carrier of a S305I mutation in the microtubule-associated protein tau (MAPT)-gene causing frontotemporal dementia. Stem Cell Res. 2016 Nov;17(3):564-567. Epub 2016 Oct 20 PubMed.
2. Bowles KR, Pedicone C, Pugh DA, Oja LM, Sousa FH, Keavey LK, Fulton-Howard B, Weitzman SA, Liu Y, Chen JL, Disney MD, Goate AM. Development of MAPT S305 mutation human iPSC lines exhibiting elevated 4R tau expression and functional alterations in neurons and astrocytes. Cell Rep. 2024 Dec 24;43(12):115013. Epub 2024 Nov 27 PubMed.
3. Kovacs GG, Pittman A, Revesz T, Luk C, Lees A, Kiss E, Tariska P, Laszlo L, Molnár K, Molnar MJ, Tolnay M, de Silva R. MAPT S305I mutation: implications for argyrophilic grain disease. Acta Neuropathol. 2008 Jul;116(1):103-18. Epub 2007 Dec 8 PubMed.
4. Langerscheidt F, Wied T, Al Kabbani MA, van Eimeren T, Wunderlich G, Zempel H. Genetic forms of tauopathies: inherited causes and implications of Alzheimer's disease-like TAU pathology in primary and secondary tauopathies. J Neurol. 2024 Jun;271(6):2992-3018. Epub 2024 Mar 30 PubMed.
5. Gil MJ, Serrano S, Manzano MS, Cuadrado ML, Góméz E, Rábano A. Argyrophilic grain disease presenting as behavioral frontotemporal dementia. Clin Neuropathol. 2019;38(1):8-13. PubMed.
6. 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.
7. Tsai RM, Bejanin A, Lesman-Segev O, LaJoie R, Visani A, Bourakova V, O'Neil JP, Janabi M, Baker S, Lee SE, Perry DC, Bajorek L, Karydas A, Spina S, Grinberg LT, Seeley WW, Ramos EM, Coppola G, Gorno-Tempini ML, Miller BL, Rosen HJ, Jagust W, Boxer AL, Rabinovici GD. 18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes. Alzheimers Res Ther. 2019 Jan 31;11(1):13. PubMed.
8. Longhini AP, DuBose A, Lobo S, Vijayan V, Bai Y, Rivera EK, Sala-Jarque J, Nikitina A, Carrettiero DC, Unger MT, Sclafani OR, Fu V, Beckett ER, Vigers M, Buée L, Landrieu I, Shell S, Shea JE, Han S, Kosik KS. Precision proteoform design for 4R tau isoform selective templated aggregation. Proc Natl Acad Sci U S A. 2024 Apr 9;121(15):e2320456121. Epub 2024 Apr 3 PubMed.
9. Strang KH, Sorrentino ZA, Riffe CJ, Gorion KM, Vijayaraghavan N, Golde TE, Giasson BI. Phosphorylation of serine 305 in tau inhibits aggregation. Neurosci Lett. 2019 Jan 23;692:187-192. Epub 2018 Nov 10 PubMed.

External Citations

1. arch et al., 2019
2. Karch et al., 2019

Further Reading

No Available Further Reading