PSEN1 M139I (G>C)


Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640352 G>C
dbSNP ID: rs63750522
Coding/Non-Coding: Coding
Genomic Region: Exon 5
Mutation Type: Point, Missense
Codon Change: ATG to ATC


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 30s and 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 that M139I is pathogenic.


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. In contrast to the eight other presenilin mutations examined in this study, pyramidal neurons in the two M139I brains showed co-localization 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/Aβ total ratio in COS-1 cells co-transfected with APP695 (Murayama et al., 1999).


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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. . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
  3. . Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease. Mol Med. 2000 Oct;6(10):878-91. PubMed.
  4. . 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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database