Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic, Progressive Supranuclear Palsy : Pathogenic
Clinical Phenotype: Frontotemporal Dementia, Progressive Supranuclear Palsy
Position: (GRCh38/hg38):Chr17:46010375 T>C
Position: (GRCh37/hg19):Chr17:44087741 T>C
dbSNP ID: rs63750912
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Silent
Codon Change: AAT to AAC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This silent mutation was first reported in a woman with a frontotemporal dementia syndrome resembling corticobasal degeneration (Spillantini et al., 2000). The mutation carrier belonged to a previously described kindred affected by early onset dementia. The reported pedigree shows four affected family members over three generations (Brown et al., 1996). Segregation with disease could not be determined. The proband experienced symptom onset at age 56, starting with personality changes, cognitive decline, and stereotyped behavior. She also developed supranuclear gaze palsy, bradykinesia, and muteness. She died at age 69, 13 years after symptom onset.

This mutation was later described in a Japanese man with probable progressive supranuclear palsy (Ogaki et al., 2012). He had a family history of neurodegenerative disease, but segregation with disease could not be determined. He developed symptoms at age 44, starting with parkinsonism. Motor symptoms included bradykinesia, rigidity, and postural instability. He developed dementia accompanied by changes in personality and behavior.

Neuropathology

Autopsy of the female proband showed marked frontotemporal atrophy with prominent neuronal loss in the globus pallidus, substantia nigra, and locus ceruleus. Swollen achromatic neurons and tau-positive inclusions were present throughout the brain. Plaques and tangles were rare in the hippocampus and cerebral cortex. Overall, the neuropathology was most consistent with corticobasal degeneration (Spillantini et al., 2000; Brown et al., 1996).

Biological Effect

The N296N silent mutation increases the inclusion of exon 10 in tau mRNA and therefore increases the ratio of 4R/3R tau protein (Spillantini et al., 2000; Grover et al., 2002).

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References

Paper Citations

1. Spillantini MG, Yoshida H, Rizzini C, Lantos PL, Khan N, Rossor MN, Goedert M, Brown J. A novel tau mutation (N296N) in familial dementia with swollen achromatic neurons and corticobasal inclusion bodies. Ann Neurol. 2000 Dec;48(6):939-43. PubMed.
2. Brown J, Lantos PL, Roques P, Fidani L, Rossor MN. Familial dementia with swollen achromatic neurons and corticobasal inclusion bodies: a clinical and pathological study. J Neurol Sci. 1996 Jan;135(1):21-30. 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.
4. Grover A, DeTure M, Yen SH, Hutton M. Effects on splicing and protein function of three mutations in codon N296 of tau in vitro. Neurosci Lett. 2002 Apr 19;323(1):33-6. PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database
2. Japanese Familial Alzheimer's Disease Database