Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:45996638 C>G
Position: (GRCh37/hg19):Chr17:44074004 C>G
dbSNP ID: rs63750349
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Missense
Codon Change: CTG to GTG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 9
Research Models: 1

Findings

This mutation 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.

This mutation 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.

This mutation was later described in a Japanese woman diagnosed with the behavioral variant of FTD (bvFTD) (Ogaki et al., 2012). The pattern of inheritance in this family was described as autosomal-dominant; however, family history details were not provided and segregation with disease could not be determined. The mutation carrier developed symptoms, primarily personality/behavioral changes and cognitive decline, at age 37.

Neuropathology

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.

Biological Effect

In vitro, this mutation alters the splicing of exon 10, resulting in higher levels of exon 10-containing tau transcripts. This splicing effect results in a relative increase in tau protein containing four microtubule binding repeat domains (4R tau). This mutation is associated with a decreased rate of tau-induced microtubule assembly and overall lower levels of tubulin polymerization. Tau assembly was found to be increased specifically for 3R tau isoforms (Kobayashi et al., 2003; Hogg et al., 2003).

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References

Paper Citations

1. 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.
2. 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.
3. 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.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database