Mutations

PSEN1 M139I (G>C)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Genomic Mutation Name (MET1): g.25620G>C
Genomic Mutation Name (NT1): g.42174G>C
dbSNP ID: rs63750522
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ATG to ATA

Findings

This mutation was reported in a Korean family with three affected individuals over two generations (Kim et al., 2010). The proband, a teacher, developed cognitive impairment at age 37. Her clinical presentation was fairly typical for AD and she met NINCDS-ADRDA criteria for probable AD (McKhann et al., 1984). She did not exhibit extrapyramidal symptoms, ataxia, myoclonus, or seizures. Her mother had developed a similar progressive cognitive decline starting in her thirties and had died at the age of 45. The proband’s oldest sister developed dementia at age 35. The mutation was detected in the proband and was absent in her three healthy siblings, suggesting M139I is pathogenic.

Neuropathology

Brain tissue from two cases carrying the M139I mutation was examined by immunohistochemistry (Mathews et al., 2000); however, it was not clear in this report whether the individuals carried the G>A or G>C version of the M139I mutation. In contrast to the eight other presenilin mutations examined in this study, pyramidal neurons in the two M139I brains showed colocalization of neurofibrillary tangles with presenilin-1 protein. The authors speculated that presenilin may become mislocalized during neurodegeneration. The expression level of presenilin-1 in the M139I cases and endoproteolysis of the protein were comparable to control brains and those with sporadic AD.

Biological Effect

In vitro, the M139I mutation increases the Aβ42/Aβtotal ratio in COS-1 cells cotransfected with APP695 (Murayama et al., 1999).

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References

Paper Citations

  1. . Presenilin 1 gene mutation (M139I) in a patient with an early-onset Alzheimer's disease: clinical characteristics and genetic identification. Neurol Sci. 2010 Dec;31(6):781-3. PubMed.
  2. . Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease. Mol Med. 2000 Oct;6(10):878-91. PubMed.
  3. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.

External Citations

  1. McKhann et al., 1984

Further Reading

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database