Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PP3, BS1
Clinical Phenotype Studied: bvFTD
Position: (GRCh38/hg38):Chr17:46018716 G>A
Position: (GRCh37/hg19):Chr17:44096082 G>A
Transcript: NM_005910; ENST00000351559
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGA to AGA
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12

Findings

This mutation was identified in an Italian family known as “DM” in which two individuals over two generations had symptoms consistent with frontotemporal dementia. The proband began experiencing symptoms at age 52, including bizarre behavior and personality changes. She later developed apathy and aggressive behavior, followed by severe language and memory disturbances, apraxia, and bradykinesia. Her mother died at age 55 following an eight-year history of dementia with prominent behavioral disturbances. No additional family history was reported. The proband was a mutation carrier and her unaffected sister was not. However, the unaffected sister’s age was not reported and Alzforum requires at least one non-carrier to remain unaffected at an age past the family’s mean age at onset (at least two standard deviations) to qualify as supportive of co-segregation with disease. In addition to MAPT, the progranulin gene, GRN, was screened, but no mutations were detected (Rossi et al., 2012).

An international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature reported one family including two presumed carriers with the behavioral variant of FTD (bvFTD) (Moore et al., 2020, suppl tables 5-6). The Rossi et al., 2012 primary study was referenced and the age at death of one of the presumed carriers matches that of the mother in the original study. Thus, it is likely these two reports refer to the same family.

This variant was reported in the gnomAD public variant database at a frequency of 0.0000082, including 12 heterozygotes of multiple ancestries (gnomAD v4.1.1, Apr 2024).

Neuropathology

Neuropathological data are unavailable. However, an MRI scan of the proband’s brain showed moderate to severe symmetrical cerebral atrophy, predominantly involving the frontal lobe with ventricular enlargement (Rossi et al., 2012).

Biological Effect

This variant is located in the fourth microtubule-binding repeat of tau. Similar to other mutants in this repeat, G366R appears to decrease microtubule binding. In the original study describing this variant, an in vitro assay using isolated proteins revealed a reduced ability to promote microtubule assembly (Rossi et al., 2012). Consistent with this finding, in HEK293T cells transfected with mutant tau containing either three (Xia et al., 2023) or four (Xia et al., 2019) microtubule-binding repeats (0N3R and 0N4R, respectively), tau binding to paclitaxel-stabilized microtubules was reduced compared to wildtype tau.

G366R appears to have little or no effect on tau aggregation, however. Mutant tau aggregation kinetics in vitro were similar to those of the wild-type protein (Rossi et al., 2012). Similarly, in transfected HEK293T cells, only a modest increase in aggregation of the mutant 0N3R tau was observed that did not reach statistical significance, and incubation with exogenous K19 peptides—tau fragments that act as aggregation seeds—did not enhance aggregation (Xia et al., 2023). Moreover, no effect on aggregation was detected for the mutant 0N4R tau isoform (Xia et al., 2019).

Of note, increased chromosomal instability and copy-number variations have been observed in lymphocytes and fibroblasts of mutation carriers (Rossi et al., 2013).

This variant's PHRED-scaled CADD score (33), which integrates diverse information in silico, was 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.

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References

Paper Citations

1. Rossi G, Bastone A, Piccoli E, Mazzoleni G, Morbin M, Uggetti A, Giaccone G, Sperber S, Beeg M, Salmona M, Tagliavini F. New mutations in MAPT gene causing frontotemporal lobar degeneration: biochemical and structural characterization. Neurobiol Aging. 2012 Apr;33(4):834.e1-6. Epub 2011 Sep 22 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. 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.
4. 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.
5. Rossi G, Conconi D, Panzeri E, Redaelli S, Piccoli E, Paoletta L, Dalprà L, Tagliavini F. Mutations in MAPT gene cause chromosome instability and introduce copy number variations widely in the genome. J Alzheimers Dis. 2013;33(4):969-82. PubMed.

Further Reading

No Available Further Reading