Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype Studied: bvFTD
Position: (GRCh38/hg38):Chr17:46010414 C>T
Position: (GRCh37/hg19):Chr17:44087780 C>T
dbSNP ID: rs63750916
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift
Codon Change: C to T
Genomic Region: Intron 10

Findings

This mutation was identified in the proband of the Kumamoto pedigree, a Japanese kindred exhibiting frontotemporal dementia (FTD) across three generations (Yasuda et al., 2000). The primary clinical characteristics were parkinsonism and dementia presenting in the fifth decade of life, with a mean age of onset of 53 years and a mean duration of illness of seven years (n=6). Only the proband of this family, with an age at onset of 56 years and a disease duration of 9 years, was genotyped. The mutation was absent from 100 controls and 50 patients with sporadic FTD.

This variant was also reported in an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature (Moore et al., 2020, suppl tables 5-6). The single carrier reported was classified as having the behavioral variant of FTD (bvFTD). Since the ages at onset and at death of this carrier were the same as those of the carrier described by Yasuda and colleagues, it is likely they are the same individual.

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

Neuropathology

Post-mortem examination of the proband’s brain revealed severe atrophy, of the frontal and temporal lobes—including neuronal loss, microvacuolation, and fibrillary astrocytosis  (Takamatsu et al., 1998, Yasuda et al 2000). These features were also observed in the brainstem, cerebellum, and subcortical gray matter. Levels of exon 10 containing tau transcripts and corresponding tau isoforms with four microtubule-binding repeats (4R), were elevated. Tau aggregates were observed in neurons and glial cells. Isolated tau filaments had twisted, ribbon-like morphology, and were comprised of hyperphosphorylated 4R tau. Pick bodies, neurofibrillary tangles, and neuritic plaques were absent.

Biological Effect

This variant resides in an inhibitory stem-loop structure formed at the E10/I10 junction that blocks access to the 5′ splice site (D’Souza and Schellenberg, 2005). The thermodynamic stability of this stem-loop is reduced by this mutation, as indicated by the mutant’s reduced melting temperature compared to that of wildtype tau RNA (Yasuda et al., 2000, Lisowiec et al., 2015). Consistent with these findings and the increased levels of 4R tau observed in the proband’s brain tissue (Yasuda et al., 2000), 4R isoforms were increased by 24 percent in cultured cells expressing mutant constructs (Lisowiec et al., 2015).

This variant's PHRED-scaled CADD score (23.3), 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 : 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

Paper Citations

1. Yasuda M, Takamatsu J, D'Souza I, Crowther RA, Kawamata T, Hasegawa M, Hasegawa H, Spillantini MG, Tanimukai S, Poorkaj P, Varani L, Varani G, Iwatsubo T, Goedert M, Schellenberg DG, Tanaka C. A novel mutation at position +12 in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto). Ann Neurol. 2000 Apr;47(4):422-9. 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. Takamatsu J, Kondo A, Ikegami K, Kimura T, Fujii H, Mitsuyama Y, Hashizume Y. Selective expression of Ser 199/202 phosphorylated tau in a case of frontotemporal dementia. Dement Geriatr Cogn Disord. 1998 Mar-Apr;9(2):82-9. PubMed.
4. D'Souza I, Schellenberg GD. Regulation of tau isoform expression and dementia. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):104-15. PubMed.
5. Lisowiec J, Magner D, Kierzek E, Lenartowicz E, Kierzek R. Structural determinants for alternative splicing regulation of the MAPT pre-mRNA. RNA Biol. 2015;12(3):330-42. PubMed.

Further Reading