Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, BP4
Clinical Phenotype Studied: bvFTD
Position: (GRCh38/hg38):Chr17:46010415 A>G
Position: (GRCh37/hg19):Chr17:44087781 A>G
dbSNP ID: rs63750308
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift
Codon Change: A to G
Genomic Region: Intron 10

Findings

This mutation was originally described in a British kindred known as MAN19 (Hutton et al., 1998). The three affected family members experienced changes in behavior and social conduct consistent with frontotemporal dementia (FTD). Apathy and inertia were prominent in one mutation carrier who developed symptoms at age 65 and had a disease duration of only five years. A similar pattern was reported in his father and sister (Pickering-Brown et al., 2002).

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). A family with two presumed carriers was reported with one having the behavioral variant of FTD (bvFTD) and one having dementia not otherwise specified. It is possible this family is the same one as described above.

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

Neuropathology

MRI showed cerebral atrophy that was most prominent in the temporal lobes. SPECT showed frontal and temporal dysfunction, particularly on the left side. Postmortem examination showed severe "knife‐edge" atrophy in the frontal and temporal lobes. Frequent neurofibrillary and glial tangles were observed, and were more moderate in the brainstem. Occasional ballooned neurons were also observed, along with damage to the substantia nigra (Pickering-Brown et al., 2002).

Biological Effect

This intronic variant resides in an inhibitory stem-loop structure formed at the junction of exon 10 and intron 10 that blocks access to the 5′ splice site (Grover et al., 1999, D’Souza and Schellenberg, 2005). The thermodynamic stability of this stem-loop is reduced by this mutation, as indicated by RNA gel migration patterns and susceptibility of mutant tau constructs to RNAse cleavage (Grover et al., 1999), as well as the mutant’s reduced melting temperature compared to that of wildtype tau RNA (Lisowiec et al., 2015). Consistent with these findings, increased incorporation of exon 10 was observed in mutant tau RNA constructs compared to wildtype constructs, as assessed by exon-trapping experiments in vitro (Hutton et al., 1998, Grover et al., 1999), and 4R isoforms were increased by 18 percent in cultured cells expressing a mutant construct (Lisowiec et al., 2015).

This variant's PHRED-scaled CADD score (16.3), which integrates diverse information in silico, was below the commonly used threshold of 20 to predict deleteriousness (CADD v1.7, Apr 2024).

Of note, this variant is naturally occurring in rodents, which may contribute to the predominance of 4R tau in the brains of adult rats and mice (Grover et al., 1999).

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. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.
2. Pickering-Brown SM, Richardson AM, Snowden JS, McDonagh AM, Burns A, Braude W, Baker M, Liu WK, Yen SH, Hardy J, Hutton M, Davies Y, Allsop D, Craufurd D, Neary D, Mann DM. Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene. Brain. 2002 Apr;125(Pt 4):732-51. 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. Grover A, Houlden H, Baker M, Adamson J, Lewis J, Prihar G, Pickering-Brown S, Duff K, Hutton M. 5' splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem. 1999 May 21;274(21):15134-43. PubMed.
5. D'Souza I, Schellenberg GD. Regulation of tau isoform expression and dementia. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):104-15. PubMed.
6. 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