Overview

Pathogenicity: Frontotemporal Dementia : Likely Pathogenic
Clinical Phenotype: bvFTD, Tauopathy consistent with Pick's Disease
Position: (GRCh38/hg38):Chr17:45996612 A>C
Position: (GRCh37/hg19):Chr17:44073978 A>C
dbSNP ID: rs63750129
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAG to ACG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 9

Findings

Th K257T mutation was first identified in an individual from England with frontotemporal dementia (FTD) who had neuropathologically confirmed Pick's disease. He developed symptoms at age 47 and died 4 years later. He first presented with memory decline followed by gradual changes in personality and behavior, namely disinhibition and erratic behavior. He also developed severe language impairments. He did not have a family history of dementia (his father died of myocardial infarction at age 79 and his mother died following a stroke at age 80). Segregation with disease could not be established, and it may be a de novo mutation (Rizzini et al., 2000; Pickering-Brown, 2000).

A second case was identified in the Sydney and Cambridge Brain Banks (Forrest et al., 2018). This individual was a 64-year-old male and had a disease duration of 4 years, with a main clinical diagnosis of the behavioral variant of FTD (bvFTD). As the other case, neuropathology confirmed Pick’s disease.

In an international, retrospective cohort study, five patients with the K257T mutation were identified in the Frontotemporal Dementia Prevention Initiative and the published literature, including four with bvFTD and one with dementia not otherwise specified (Moore et al., 2020). The five patients identified in this report were derived from 3 families. It is not clear whether these five include the two patients previously discussed. Also of note, the study included both confirmed mutation carriers, as well as family members who were assumed to be carriers based on their clinical phenotype. The mean age of disease onset was 46.3 years (n=4), the mean age at death was 54.0 years (n=3), and the mean disease duration was 6.3 years (n=3).

In the gnomAD variant database, this variant was reported at a global frequency of 0.0000021, including three heterozygotes of European (non-Finnish) ancestry (gnomAD v.4.1.0, April 2024).

Neuropathology

In the first case introduced above of the 47-year-old man from England, autopsy showed Pick’s disease, a subtype of FTD. Severe frontotemporal atrophy was observed, especially in the temporal lobes. Numerous tau-positive Pick bodies were seen in the neocortex, hippocampus, and some subcortical regions. Diffuse hyperphosphorylated tau was observed in some cell bodies (Rizzini et al., 2000).

In the second case of the 64-year-old, neuropathological hallmarks of Pick’s disease were also observed, including Pick bodies, balloon neurons, ramified astrocytes, threads, coiled bodies, and globular oligodendroglial inclusions in the gray and white matter (Forrest et al., 2018). Additional observations included deposition of the 3R isoform of tau and neuronal loss in the superior frontal cortex, inferior temporal cortex, entorhinal cortex, CA1 of hippocampus, and midbrain.

Biological Effect

Recombinant tau protein with the K257T mutation—located in the first repeat domain of 4R tau within the microtubule assembly domain—showed reduced ability to promote microtubule assembly (Rizzini et al., 2000). Another study using recombinant K257T protein also demonstrated significantly reduced microtubule assembly, based on the maximum rate of microtubule formation as well as the extent of assembly for both 2N3R and 2N4R tau isoforms (Grover et al., 2003).

In addition, in silico analyses predicted the mutation diminishes cathepsin cleavage which was confirmed in vitro using protease assays (Sampognaro et al., 2023). Consistent with these findings, the lysosomal degradation of mutant tau in neuronal-like SH-SY5Y cells was reduced.

Moreover, K257 is one of the lysines in K18, a region containing the four repeat domains of tau. K18 lysines have been implicated in the binding of LRP1 (low-density lipoprotein receptor-related protein 1), a receptor involved in endocytosis of tau (Rauch et al., 2020; March 2020 conference news). Thus, it is possible that the K257T substitution can affect tau endocytosis and spread, but this would need to be experimentally confirmed.

Tau aggregation, however, does not seem to be affected by the mutation. As measured with thioflavin-S fluorescence, tau aggregation was not significantly increased in recombinant K257T protein on 2N3R and 2N4R tau isoforms (Grover et al., 2003). Another study used a tau seeding model with mutant HEK293T cells to examine the propensity of the K257T variant to form inclusions (Strang et al., 2018). Consistent with the in vitro findings above, in K257T-expressing cells that were exposed to fibrils of wild-type K18 tau peptides, which are aggregation-prone, tau did not accumulate, indicating a lack of seeding and tau inclusion formation. Moreover, the K257T mutation does not appear to affect Cdk5-mediated phosphorylation of tau, as suggested by both in vitro and cell-based assays (Sakaue et al., 2005).

K257T’s PHRED-scaled CADD score, which integrates diverse information in silico, was 19.98, very close to the threshold of 20 commonly used for predicting deleteriousness (CADD v1.7, Apr 2024).

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References

News Citations

1. Tau Receptor Identified on Cell Surface 7 Mar 2020

Paper Citations

1. Rizzini C, Goedert M, Hodges JR, Smith MJ, Jakes R, Hills R, Xuereb JH, Crowther RA, Spillantini MG. Tau gene mutation K257T causes a tauopathy similar to Pick's disease. J Neuropathol Exp Neurol. 2000 Nov;59(11):990-1001. PubMed.
2. Pickering-Brown S, Baker M, Yen SH, Liu WK, Hasegawa M, Cairns N, Lantos PL, Rossor M, Iwatsubo T, Davies Y, Allsop D, Furlong R, Owen F, Hardy J, Mann D, Hutton M. Pick's disease is associated with mutations in the tau gene. Ann Neurol. 2000 Dec;48(6):859-67. PubMed.
3. Forrest SL, Kril JJ, Stevens CH, Kwok JB, Hallupp M, Kim WS, Huang Y, McGinley CV, Werka H, Kiernan MC, Götz J, Spillantini MG, Hodges JR, Ittner LM, Halliday GM. Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. Brain. 2018 Feb 1;141(2):521-534. PubMed.
4. 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.
5. Grover A, England E, Baker M, Sahara N, Adamson J, Granger B, Houlden H, Passant U, Yen SH, DeTure M, Hutton M. A novel tau mutation in exon 9 (1260V) causes a four-repeat tauopathy. Exp Neurol. 2003 Nov;184(1):131-40. PubMed.
6. Sampognaro PJ, Arya S, Knudsen GM, Gunderson EL, Sandoval-Perez A, Hodul M, Bowles K, Craik CS, Jacobson MP, Kao AW. Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases. Mol Neurodegener. 2023 May 2;18(1):29. PubMed. Correction.
7. Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, Leshuk C, Hernandez I, Wegmann S, Hyman BT, Gradinaru V, Kampmann M, Kosik KS. LRP1 is a master regulator of tau uptake and spread. Nature. 2020 Apr;580(7803):381-385. PubMed.
8. Strang KH, Croft CL, Sorrentino ZA, Chakrabarty P, Golde TE, Giasson BI. Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies. J Biol Chem. 2018 Feb 16;293(7):2408-2421. Epub 2017 Dec 19 PubMed.
9. Sakaue F, Saito T, Sato Y, Asada A, Ishiguro K, Hasegawa M, Hisanaga S. Phosphorylation of FTDP-17 mutant tau by cyclin-dependent kinase 5 complexed with p35, p25, or p39. J Biol Chem. 2005 Sep 9;280(36):31522-9. Epub 2005 Jul 1 PubMed.

Further Reading

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