Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP3
Clinical Phenotype Studied: Alzheimer's Disease, Corticobasal Syndrome, bvFTD, ALS-FTD, Pick's disease, Parkinsonism
Position: (GRCh38/hg38):Chr17:46018628 G>C
Position: (GRCh37/hg19):Chr17:44095994 G>C
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs1598408073
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAG to CAC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This mutation was identified in a man from the U.S. with neuropathologically confirmed Pick's disease (Tacik et al., 2015). He died at age 63, eight years after symptom onset. He first presented with deficits in short-term memory and personality changes with disinhibition. He later developed speech hesitancy, word-finding difficulties, and parkinsonism, including bradykinesia, rigidity, and an unsteady gait. Clinically, he was diagnosed with atypical Alzheimer’s disease (AD) with parkinsonism, but he had neuropathology consistent with Pick’s disease (see “Neuropathology” below). Also of note, a subsequent paper described this carrier’s phenotype as behavioral variant frontotemporal dementia bvFTD with parkinsonism (Villa et al., 2022).

In addition to carrying the Q336H mutation, the proband was homozygous for the H1 MAPT haplotype (Tacik et al., 2015). He had a positive family history for early-onset neurodegenerative disease. His mother had a similar clinical syndrome and died at age 65. His maternal uncle had been diagnosed with AD. Genetic and neuropathological analyses were not available for these two family members.

A carrier of another mutation resulting in the same amino acid substitution, Q336H (G>T), was also diagnosed with an AD-like disorder (Villa et al., 2022). However, his son, who also carried the mutation, was diagnosed with the semantic variant of primary progressive aphasia (svPPA).

A large international retrospective cohort study that included data collected by the Frontotemporal Dementia Prevention Initiative and the published literature, listed three families with five Q336H carriers (Moore et al., 2020, suppl 1). The nucleotide change was unspecified, but one of the families was the one described by Tacik and colleagues (Tacik et al., 2015). Two of the carriers from the cohort study were described as having frontotemporal dementia/amyotrophic lateral sclerosis (FTD-ALS), one corticobasal syndrome (CBS), and two dementia not otherwise specified (Moore et al., 2020). The mean age of disease onset was 61.5 years and the mean duration of disease was 5.0 years. Of note, this study included both confirmed mutation carriers and family members who were assumed to be carriers based on their clinical phenotype.

A single heterozygous carrier of non-Finnish European ancestry was reported in the gnomAD public variant database (v.4.1.0, April 2024).

Neuropathology
The proband met neuropathological criteria for Pick's disease (Tacik et al., 2015). Postmortem examination showed focal cortical atrophy and frequent well-characterized Pick bodies in the upper cortical layers. Pick bodies were cytoplasmic neuronal inclusions that were largely negative for Gallyas silver stain. They were immunopositive for 3R tau (tau isoforms containing three microtubule-binding repeat domains); a minority contained 4R tau. Tau protein within Pick bodies was arranged in randomly oriented straight filaments with a diameter of 10 to 15 nm, with a few larger twisted filaments.

Pick cells, called “swollen achromatic neurons” or “ballooned neurons,” were frequent in the middle and lower neocortical layers of the frontal and temporal lobes.

Biological Effect
Unlike many other MAPT pathogenic variants, Q336H appears to increase, rather than decrease, the binding of tau to microtubules. In vitro experiments using recombinant tau indicated the Q336H mutation facilitated tau binding to microtubules and promoted microtubule polymerization (Tacik et al., 2015). Compared with wild-type tau protein, mutant 3R and 4R tau proteins were associated with faster microtubule polymerization and higher steady-state levels of polymerization.

Subsequent experiments in HEK293T cells treated with paclitaxel to promote microtubule polymerization also indicated increased microtubule binding (Xia et al., 2021). However, in this case, the effect was observed only for 0N3R, not 0N4R, tau. Interestingly, decreased levels of tyrosinated tubulin were found in cells expressing 0N3R, but not 0N4R, tau with no change in acetylation levels for either isoform. Tyrosinylation is a post-translational modification associated with newly formed microtubules that helps maintain microtubule dynamics and recruit motor proteins for axonal transport, whereas acetylation is a marker of microtubule stability.

Fluorescence resonance energy transfer (FRET) assays to monitor tau folding in transfected HeLa cells have also suggested Q336H enhances tau’s interaction with microtubules. In cells expressing the 4R mutant protein, tau’s N- and C-termini were more often in proximity, consistent with a tubulin-bound conformation (Siano et al., 2020). Also, in experiments using fluorescence recovery after photobleaching (FRAP), the mobile fraction of mutant tau was reduced compared to that of cells expressing wildtype tau, suggesting the mutant protein has a more stable interaction with tubulin. Moreover, network analysis of tubulin filament length and branching points showed increases in both parameters associated with mutant tau expression.

Under some circumstances, Q336H may also fuel tau aggregation. For example, Tacik and colleagues observed an increase in polyglycosaminoglycan-induced assembly of tau filaments in vitro (Tacik et al., 2015). This effect was observed for both 3R and 4R isoforms, but was greater for 3R tau, consistent with the observation that Pick bodies are largely comprised of 3R tau.

Moreover, when treated with preformed P301S seeds, HeLa cells transfected with mutant, but not wildtype, 4R tau developed intracellular inclusions that were positively stained with K114, a fluorescent probe used to detect amyloid fibrils (Siano et al., 2020). However, in transfected HEK293T cells, neither mutant nor wildtype 0N4R tau developed aggregates (Xia et al., 2021). The addition of aggregation-prone K18 seeds failed to induce aggregation. Furthermore, although the mutant 0N3R isoform formed some aggregates when K19 seeds were added, the effect was not statistically significant, but it was, surprisingly, for wild-type 0N3R tau.

Q336H does not appear to enhance tau phosphorylation and may, in fact, reduce it. Tau phosphorylated at S396/S404 was identified in the insoluble fraction of HEK293T cells expressing either mutant or wildtype 0N3R tau (Xia et al., 2021). Neither the mutant nor wildtype 0N4R tau isoform was significantly phosphorylated at these sites. Moreover, in HeLa cells, phosphorylation of 4R tau at S202/T205, S262, and T231 was reduced in cells expressing the mutant protein compared to those expressing wildtype tau (Siano et al., 2020).

This variant’s PHRED-scaled CADD score which integrates diverse information in silico, was 23.3, above the commonly used deleteriousness threshold of 20 (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Not Classified*

*This variant fulfilled several ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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

Mutations Citations

1. MAPT Q336H (G>T)

Paper Citations

1. Tacik P, DeTure M, Hinkle KM, Lin WL, Sanchez-Contreras M, Carlomagno Y, Pedraza O, Rademakers R, Ross OA, Wszolek ZK, Dickson DW. A Novel Tau Mutation in Exon 12, p.Q336H, Causes Hereditary Pick Disease. J Neuropathol Exp Neurol. 2015 Nov;74(11):1042-52. PubMed.
2. Villa C, Rossi G, Bizzozero I, Prioni S, Boiocchi C, Agosta F, Canu E, Filippi M, Giaccone G, Caroppo P. MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family. Eur J Neurol. 2022 May;29(5):1529-1533. Epub 2022 Jan 31 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. Xia Y, Nasif L, Giasson BI. Pathogenic MAPT mutations Q336H and Q336R have isoform-dependent differences in aggregation propensity and microtubule dysfunction. J Neurochem. 2021 Jul;158(2):455-466. Epub 2021 Apr 12 PubMed.

Other Citations

1. Siano et al., 2020

Further Reading

No Available Further Reading