Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS4, PM1, PM2, PP3
Clinical Phenotype Studied: Alzheimer's Disease, bvFTD
Position: (GRCh38/hg38):Chr17:46018672 A>G
Position: (GRCh37/hg19):Chr17:44096038 A>G
Transcript: NM_005910; ENST00000351559
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAG to CGG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This variant has been identified in several individuals with frontotemporal dementia (FTD), with some carriers showing features of Alzheimer's disease (AD).

It was first identified in a woman in the U.K. with a family history suggestive of a dominantly inherited neurodegenerative disease—her father and two of his siblings developed apathy and memory loss in middle age (Liang et al., 2014). Before the identification of the MAPT Q351R variant, when she was suspected of having AD, the woman was screened for mutations in APP, PSEN1 and PSEN2 but none were found. In a subsequent international, retrospective cohort study, two individuals who appear to correspond to members of this family were described as having behavioral variant of FTD (bvFTD) (Moore et al., 2020 suppl).

The variant was subsequently reported in three Chinese women. Two women, of Han Chinese ancestry, were diagnosed with behavioral variant FTD (bvFTD) with ages at onset of 45 and 51 years (Nan et al., 2024). The third woman was diagnosed with FTD with an age at onset of 46 (Li et al., 2024). This carrier had a 10-year history of progressive memory loss with personality changes, including irritability, emotional lability, lack of empathy, and apathy. Of note, an apparent lack of amyloid pathology, suggested by 18F-florbetapir PET imaging, helped rule out an AD diagnosis.

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

Neuropathology

Post-mortem analysis of the UK carrier revealed tau pathology involving 3-repeat (3R) and 4-repeat (4R) tau isoforms with neurofibrillary tangles most prominent in the medial temporal lobes (Drazich-Taylor et al., 2023). This was consistent with previous data from (18F)AV-1451 PET imaging which initially suggested 3R/4R tauopathy in the cortical insular region and the medial temporal, putamen and pallidum subcortical regions (Convery et al., 2020). A year later, the tau signal had increased in these regions and spread to the cortical temporal region and subcortical caudate and thalamus. The signal was described as similar to that seen in both Alzheimer’s disease and a subgroup of MAPT mutations (R406W and V337M). In the post-mortem examination, tau immunohistochemistry showed hyperphosphorylated tau present in neurofibrillary tangles, neuropil threads, and small dot-like deposits (Drazich-Taylor et al., 2023). Tau pathology was most severe in the temporal lobe, particularly in the fusiform and parahippocampal gyri, as well as in the amygdala and hippocampus. Tau deposits were also observed in the basal ganglia, brainstem, and dentate nucleus. Mild amyloid-β deposition and mild cerebrovascular disease were seen in the cerebral cortex.

Examination at autopsy also showed frontotemporal cerebral atrophy, particularly severe in the anterior medial temporal lobes (Drazich-Taylor et al., 2023). This observation was also consistent with previously acquired imaging data (Liang et al.,  2014). Longitudinal MR imaging—performed at baseline (when the patient was 49 years of age), and four and ten years later—showed progressive brain atrophy, particularly of the temporal lobes, with a whole brain atrophy rate of 0.7 percent per year. Initial atrophy localized to medial temporal areas, mostly affecting the amygdala and anterior hippocampus, and subsequently the temporal and insular cortices, followed by the frontal and anterior cingulate cortices, as well as the striatum. Posterior cortical regions were relatively unaffected. 

In one Chinese carrier, 18F-FDG PET revealed hypometabolism in the medial temporal lobes (Li et al., 2024). Accumulation of tau, as revealed by 18F-florzolotau PET, differed somewhat from that reported in the U.K. carrier, with affected areas including the medial temporal lobes, basal ganglia, brainstem, and cerebellum. As stated above, 18F-florbetapir PET imaging showed no pathologic amyloid accumulation.

MR imaging of two Chinese carriers revealed bilateral frontal and temporal lobe atrophy (Nan et al., 2024).

Biological Effect

Amino acid 351 is located  in the fourth microtubule-binding domain of tau. The biological effect of the glutamine-to-arginine substitution has not been tested directly.

Several in silico analyses (SIFT, Polyphen-2, MutationTaster) predicted this variant is damaging (Liang et al.,  2014; Nan et al., 2024). Moreover, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (24.7), suggesting a deleterious effect (CADD v.1.7, Jul 2024). 

Following the ACMG-AMP guidelines, Nan and colleagues classified this variant as pathogenic and reported that ClinVar classified it as likely pathogenic (Nan et al., 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Likely Pathogenic

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 R406W
2. MAPT V337M

Paper Citations

1. Liang Y, Gordon E, Rohrer J, Downey L, de Silva R, Jäger HR, Nicholas J, Modat M, Cardoso MJ, Mahoney C, Warren J, Rossor M, Fox N, Caine D. A cognitive chameleon: lessons from a novel MAPT mutation case. Neurocase. 2014;20(6):684-94. Epub 2013 Sep 2 PubMed.
2. 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.
3. Nan H, Kim YJ, Chu M, Li D, Li J, Jiang D, Wu Y, Ohtsuka T, Wu L. Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations. Alzheimers Res Ther. 2024 Jun 13;16(1):127. PubMed.
4. Drazich-Taylor EH, Todd E, Convery R, Bocchetta M, Clarke M, Warren JD, Fox NC, Revesz T, Rohrer JD. Q351R MAPT mutation is associated with a mixed 3R/4R tauopathy and a slowly progressive cognitive, behavioural and parkinsonian syndrome. J Neurol Neurosurg Psychiatry. 2023 Feb;94(2):169-171. Epub 2022 Oct 13 PubMed.
5. Convery RS, Jiao J, Clarke MT, Moore KM, Koriath CA, Woollacott IO, Weston PS, Gunn R, Rabiner I, Cash DM, Rossor MN, Warren JD, Fox NC, Ourselin S, Bocchetta M, Rohrer JD. Longitudinal (18F)AV-1451 PET imaging in a patient with frontotemporal dementia due to a Q351R MAPT mutation. J Neurol Neurosurg Psychiatry. 2020 Jan;91(1):106-108. Epub 2019 Aug 22 PubMed.

Other Citations

1. Li et al., 2024

Further Reading

No Available Further Reading