Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP3
Clinical Phenotype Studied: CBS, Progressive Supranuclear Palsy, nfvPPA, bvFTD, Pick's disease
Position: (GRCh38/hg38):Chr17:45996638 C>G
Position: (GRCh37/hg19):Chr17:44074004 C>G
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750349
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to GTG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 9
Research Models: 1

Findings

Carriers of L266V, including multiple individuals of different ancestries, have been reported to develop disorders within the frontotemporal disease (FTD) spectrum at an early age. The variant was originally identified in a Japanese man who developed difficulties speaking and reading at age 34 (Kobayashi et al., 2003). He developed a rapidly progressive frontotemporal dementia with personality changes, disorientation, and semantic dementia. He died at age 40. The proband's mother developed personality changes at age 31 and died at age 36. The proband's brother developed personality changes and apathy at age 38. Both affected siblings carried the mutation. DNA from the mother was unavailable.

The same year, this variant was also decribed in a male proband who was diagnosed with FTD (Hogg et al., 2003). His symptoms manifested at age 33 as concentration difficulties, apathy, and disinhibition. He later developed extrapyramidal signs such as bradykinesia and poor postural reflexes. He became mute and died within four years of symptom onset. He did not have a family history of dementia, but records indicate his mother had died at age 40 following a four-year history of motor impairment attributed to multiple sclerosis.

Since then, additional carriers have been identified with clinical phenotypes in the FTD spectrum. For example, four carriers from the Chinese PUMCH Cohort had prominent personality and behavioral changes with ages at onset between 31 and 40 (Mao et al., 2021). Three had aphasia with a family history of disease and one had the behavioral variant of FTD (bvFTD) with pyramidal signs. In addition, a Japanese woman diagnosed with bvFTD with a family history of disease was reported (Ogaki et al., 2012), as well as a Korean carrier with probable nonfluent/agrammatic primary progressive aphasia (PPA) and a family history of disease consistent with autosomal dominant inheritance (Sung et al., 2021). Carriers in Brazil have also been identified—with FTD, progressive supranuclear palsy (PSP), corticobasal syndrome (Rivas-Grajales et al., 2025), and bvFTD (Acosta-Uribe et al., 2024). Moreover, in a U.S. study that analyzed the MAPT sequences of 4,366 individuals with amyotrophic lateral sclerosis (ALS), two carriers of L266V were identified (Petrozziello et al., 2022).

A large international retrospective cohort study, conducted through the Frontotemporal Dementia Prevention Initiative and published literature, listed four families with eight L266V carriers (Moore et al., 2020, suppl 1). Four presented with bvFTD, another with the semantic variant of primary progressive aphasia (svPPA), two with dementia not specified, and one with a neurological disorder not specified. The mean age of disease onset was 32.4 years and the mean duration of disease was 4.7 years. The degree of overlap with the families described above is unknown. Of note, this study included both confirmed mutation carriers and family members who were assumed to be carriers based on their clinical phenotype.

This variant was absent from the gnomAD public variant database (gnomAD v4.1.0, Apr 2024).

Neuropathology

The neuropathology reported in L266V carriers to date is consistent with FTD. One autopsied case showed severe frontotemporal atrophy along with Pick-like pathology (Kobayashi et al., 2003). In addition to severe atrophy in the frontal and temporal cortices, significant atrophy was observed in the caudate nucleus and substantia nigra. Abundant tau-positive inclusions were observed in both neurons and astrocytes. Tau-positive astrocytes with stout filaments were especially abundant in the substantia nigra. Tau-positive neurons were diffusely present in all cortical layers and even in the brainstem. Tau-positive neuronal threads and coiled bodies were also observed. Some ballooned neurons were present in the cerebral cortex.

Another autopsied case showed similar pathology (i.e., severe frontotemporal atrophy along with Pick-like pathology) (Hogg et al., 2003). Severe atrophy was also present in the hippocampus and the parietal lobe, with relative sparing of the sensory and motor gyri. There was severe neuronal loss in the cortex and substantia nigra along with gliosis. Tau-positive neuronal inclusions were widespread, including in the hippocampus, striatum, and substantia nigra. Pick bodies were Gallyas silver-positive and contained straight filaments. They were randomly distributed throughout the layers of the cortex.

In this study, tau isoforms with both three (3R) and four (4R) microtubule-binding repeats were detected in the brain. Both isoforms were present in sarkosyl-insoluble tau fractions, with a predominance of 4R tau in sarkosyl-soluble brain fractions, especially the 0N4R tau isoform (Hogg et al., 2003). Moreover, the ratio of tau RNA containing exon 10 (encoding the 4th repeat) to RNA without exon 10 in the brain was increased (Hogg et al., 2003, Kobayashi et al., 2003).

Of note, Pick bodies are typically composed of 3R tau. Consistent with this, Hogg and colleagues observed that the Pick bodies were labeled with RD3, an antibody specific for 3R tau isoforms, while thread-shaped inclusions and glia were labeled with ET3, an antibody specific for 4R tau isoforms. Moreover, a subsequent study of tissue from the same carrier confirmed the presence of 3R tau in neuronal Pick bodies and found an abundance of 4R tau in astrocytes (De Silva et al., 2006).

Also of note, in post-mortem brain tissue from one carrier, PICALM—a clathrin-adaptor protein involved in endocytosis and autophagy—was reduced in its soluble form, co-precipitated with phosphorylated tau (PHF-1), and was observed in 40 percent of Pick-like bodies (Ando et al., 2020).

Neuroimaging results have been consistent with the post-mortem findings. Brain scans of the four Chinese carriers and the Korean carrier, for example, all showed signs of typical FTD atrophy (Mao et al., 2021; Sung et al., 2021). In at least two cases, atrophy was asymmetric with the right side being more affected in a bvFTD patient who also had subcortical white matter hyperintensities, and the left side being more affected in a patient with aphasia (Mao et al., 2021). Motor involvement was suspected in two carriers.

Biological Effect
This variant appears to alter microtubule assembly and fuel aggregation, with uncertain effects on splicing. As assessed in vitro, this mutation decreased the initial rate of tau-induced microtubule assembly, as well as the overall extent of tubulin polymerization in both 2N3R and 2N4R tau isoforms (Hogg et al., 2003, Kobayashi et al., 2003). Moreover, electron microscopic analyses of tau aggregation in vitro revealed the 2N3R mutant protein enhanced tau polymerization compared to wildtype 2N3R, although the effect of the mutation on the 2N4R isoform did not reach statistical significance (Hogg et al., 2003).

As described above, carriers of this variant have increased protein and RNA levels of 4R tau relative to 3R tau. However, a study that relied on splicing assays using mini gene constructs (including exons 9 to 11) found no evidence of altered splicing, but the data were not shown (Hogg et al., 2003). Moreover, in contrast to the locations of other MAPT mutations that affect exon 10 splicing, L266V is in exon 9, far from the exon 10 splice site.

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (23.4), suggesting a deleterious effect (CADD v1.7, Apr 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Pathogenic*

*Clinical phenotypes varied between carriers.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Research Models

Researchers have generated an induced pluripotent stem cell line from a L266V carrier with FTD (Cai et al., 2022). In addition, this variant has been used, together with MAPT V337M, to create cell models that test tau seeding and propagation (Woerman et al., 2016; Dec 2016 news; Pahrudin Arrozi et al., 2021).

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References

Mutations Citations

1. MAPT V337M

Paper Citations

1. Cai H, Pang Y, Jia L. Generation of an induced pluripotent stem cell line (ICNDXHi001-A) from a patient with frontotemporal dementia carrying a heterozygous mutation c.796C > G (p.L266V) in MAPT. Stem Cell Res. 2022 Mar;59:102654. Epub 2022 Jan 3 PubMed.
2. Woerman AL, Aoyagi A, Patel S, Kazmi SA, Lobach I, Grinberg LT, McKee AC, Seeley WW, Olson SH, Prusiner SB. Tau prions from Alzheimer's disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):E8187-E8196. Epub 2016 Nov 28 PubMed.
3. Pahrudin Arrozi A, Yanagisawa D, Kato T, Akatsu H, Hashizume Y, Kaneda D, Tooyama I. Nasal Extracts from Patients with Alzheimer's Disease Induce Tau Aggregates in a Cellular Model of Tau Propagation. J Alzheimers Dis Rep. 2021 Apr 6;5(1):263-274. PubMed.
4. Kobayashi T, Ota S, Tanaka K, Ito Y, Hasegawa M, Umeda Y, Motoi Y, Takanashi M, Yasuhara M, Anno M, Mizuno Y, Mori H. A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology. Ann Neurol. 2003 Jan;53(1):133-7. PubMed.
5. Hogg M, Grujic ZM, Baker M, Demirci S, Guillozet AL, Sweet AP, Herzog LL, Weintraub S, Mesulam MM, LaPointe NE, Gamblin TC, Berry RW, Binder LI, de Silva R, Lees A, Espinoza M, Davies P, Grover A, Sahara N, Ishizawa T, Dickson D, Yen SH, Hutton M, Bigio EH. The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy. Acta Neuropathol. 2003 Oct;106(4):323-36. Epub 2003 Jul 19 PubMed.
6. Mao C, Dong L, Li J, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Cui L, Gao J. Phenotype Heterogeneity and Genotype Correlation of MAPT Mutations in a Chinese PUMCH Cohort. J Mol Neurosci. 2021 May;71(5):1015-1022. Epub 2020 Oct 1 PubMed.
7. Ogaki K, Li Y, Takanashi M, Ishikawa KI, Kobayashi T, Nonaka T, Hasegawa M, Kishi M, Yoshino H, Funayama M, Tsukamoto T, Shioya K, Yokochi M, Imai H, Sasaki R, Kokubo Y, Kuzuhara S, Motoi Y, Tomiyama H, Hattori N. Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS. Parkinsonism Relat Disord. 2012 Jul 18; PubMed.
8. Sung W, Kim YE, Kim SH. Hereditary Frontotemporal Dementia Linked to the Pathogenic p.L266V Variant of the MAPT Gene in Korea. J Clin Neurol. 2021 Jul;17(3):478-480. PubMed.
9. Rivas-Grajales AM, Han SC, Wang R, Greenstein P, Shih LC. L266V MAPT Gene Mutation Associated With Frontotemporal Dementia, Progressive Supranuclear Palsy, and Corticobasal Syndrome. J Neuropsychiatry Clin Neurosci. 2025;37(3):274-278. Epub 2025 Jan 10 PubMed.
10. Acosta-Uribe J, PinaEscudero SD, Cochran JN, Taylor JW, Castruita PA, Jonson C, Barinaga EA, Roberts K, Levine AR, George DS, Avila-Funes JA, Behrens MI, Bruno MA, Brusco LI, Custodio N, Duran-Aniotz C, Lopera F, Matallana DL, Slachevsky A, Takada LT, Zapata-Restrepo LM, Duron-Reyes DE, FrancaResende Ed, Gelvez N, Godoy ME, Maito MA, Javandel S, Miller BL, Nalls MA, Leonard H, Vitale D, Bandres-Ciga S, Koretsky MJ, Singleton AB, Pantazis CB, Valcour V, Ibanez A, Kosik K. Genetic Contributions to Alzheimer's Disease and Frontotemporal Dementia in Admixed Latin American Populations. 2024 Nov 01 10.1101/2024.10.29.24315197 (version 1) medRxiv.
11. Petrozziello T, Amaral AC, Dujardin S, Farhan SM, Chan J, Trombetta BA, Kivisäkk P, Mills AN, Bordt EA, Kim SE, Dooley PM, Commins C, Connors TR, Oakley DH, Ghosal A, Gomez-Isla T, Hyman BT, Arnold SE, Spires-Jones T, Cudkowicz ME, Berry JD, Sadri-Vakili G. Novel genetic variants in MAPT and alterations in tau phosphorylation in amyotrophic lateral sclerosis post-mortem motor cortex and cerebrospinal fluid. Brain Pathol. 2022 Mar;32(2):e13035. Epub 2021 Nov 14 PubMed.
12. 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.
13. de Silva R, Lashley T, Strand C, Shiarli AM, Shi J, Tian J, Bailey KL, Davies P, Bigio EH, Arima K, Iseki E, Murayama S, Kretzschmar H, Neumann M, Lippa C, Halliday G, MacKenzie J, Ravid R, Dickson D, Wszolek Z, Iwatsubo T, Pickering-Brown SM, Holton J, Lees A, Revesz T, Mann DM. An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies. Acta Neuropathol. 2006 Apr;111(4):329-40. Epub 2006 Mar 22 PubMed.
14. Ando K, De Decker R, Vergara C, Yilmaz Z, Mansour S, Suain V, Sleegers K, de Fisenne MA, Houben S, Potier MC, Duyckaerts C, Watanabe T, Buée L, Leroy K, Brion JP. Picalm reduction exacerbates tau pathology in a murine tauopathy model. Acta Neuropathol. 2020 Apr;139(4):773-789. Epub 2020 Jan 10 PubMed.

Other Citations

1. Dec 2016 news

Further Reading

No Available Further Reading