Overview

Pathogenicity: Frontotemporal Dementia : Likely Pathogenic
Clinical Phenotype: bvFTD
Position: (GRCh38/hg38):Chr17:46018672 A>G
Position: (GRCh37/hg19):Chr17:44096038 A>G
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

Research Models

The carrier had 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. 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.

The variant was subsequently reported in three Chinese women. Two women, of Han Chinese ancestry, were diagnosed with 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).

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References

Mutations Citations

1. MAPT R406W
2. MAPT V337M

Paper Citations

1. 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.
2. Li Q, Li H, Huang Z, Li Y, Cui R. A Peculiar Tau Accumulation Pattern Identified Via 18 F-Florzolotau PET Imaging in a Patient With Frontotemporal Dementia Caused by a Mutation in the MAPT Gene. Clin Nucl Med. 2024 Oct 1;49(10):995-996. Epub 2024 Jul 15 PubMed.
3. 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.
4. 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.
5. 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.

Further Reading

No Available Further Reading