Mutations

MAPT N296H

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Genomic Mutation Name (MET1): g.123774A>C
Genomic Mutation Name (NT1): g.120953A>C
dbSNP ID: rs63750416
Coding/Non-Coding: Coding
Genomic Region: Exon 10
Mutation Type: Point, Missense
Codon Change: AAT to CAT

Findings

The N296H mutation leads to a clinical syndrome similar to autosomal dominant frontotemporal dementia with parkisonism linked to chromosome 17. It was initially identified in a 62-year-old Japanese man who presented with frontal signs followed by temporal signs and parkinsonism (Iseki et al., 2001).

Neuropathology

The mutation is associated with localized frontotemporal lobe atrophy, including severe neuronal loss in the precentral gyrus. In the cerebral cortex, there was a proliferation of tau-positive astrocytes, but no tau-positive neurofibrillary tangles or Pick bodies. Phosphorylated tau accumulated in both neurons and glia, but was not always assembled into abnormal filaments. There was an accumultation of 4-repeat (4R) tau isoforms in the brain (Iseki et al., 2001).

Biological Effect

Position 296 falls within a region that regulates exon 10 alternative splicing. The N296H mutation increases the splicing of exon 10. It also has been shown to reduce the ability of tau to promote tubulin polymerization and microtubule assembly without affecting tau filament formation (Yoshida et al., 2002; Grover et al., 2002).

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References

Paper Citations

  1. . Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells. Acta Neuropathol. 2001 Sep;102(3):285-92. PubMed.
  2. . Functional effects of tau gene mutations deltaN296 and N296H. J Neurochem. 2002 Feb;80(3):548-51. PubMed.
  3. . 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

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Primary Papers

  1. . Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells. Acta Neuropathol. 2001 Sep;102(3):285-92. PubMed.

Other mutations at this position

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