Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease, Ataxia
Reference Assembly: GRCh37 (105)
Position: Chr14:73640284 C>G
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CCA to GCA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5


This mutation was first reported in a family with three members affected by early onset progressive ataxia and dementia (Anheim et al., 2007). The clinical phenotype in this family was fairly homogenous, with onset before age 35 and death between 35 and 40 years. The proband developed balance, writing, and memory problems at age 34. Her father developed symptoms at age 29, including tremor and problems with gait. The proband’s paternal grandmother reportedly experienced onset at age 24, including gait ataxia and balance impairment, and died at age 35. The mutation was detected in the proband, but not in her unaffected mother. The other two affected individuals could not be genotyped as they were predeceased. The proband also carried a known polymorphism in PSEN1, E318G, which was initially thought to be benign, but has subsequently been associated with increased risk of late-onset AD (Benitez et al., 2013).

Ataxia was not among the symptoms reported in a Colombian pedigree found to carry the P117A mutation. As reported, the  pedigree contained eight individuals over four generations who developed dementia during the fourth decade of life. The proband developed progressive memory impairment with gradual onset at 32 years of age and met NINCDS-ADRDA criteria for probable Alzheimer’s disease. Transmission of AD in this family is consistent with autosomal-dominant inheritance (Kauwe et al., 2008).

A French mutation carrier developed AD symptoms at 34 years of age and subsequently experienced seizures at age 41 (Zarea et al. 2016). 



Biological Effect

In vitro, the Aβ42/Aβ total ratio was higher in HEK cells expressing P117A than in cells expressing wild-type PSEN1 (Kauwe et al., 2008). Consistent with this observation, a greater than 10-fold increase in the Aβ42/Aβ0 ratio was reported using purified proteins to test the mutant's ability to process the APP-C99 substrate (Sun et al., 2017). Kauwe et al. found no significant difference in total Aβ levels, however, Sun et al. reported robust reductions in both Aβ42 and Aβ40 production.


Last Updated: 24 Nov 2019


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Paper Citations

  1. . Ataxic variant of Alzheimer's disease caused by Pro117Ala PSEN1 mutation. J Neurol Neurosurg Psychiatry. 2007 Dec;78(12):1414-5. PubMed.
  2. . The PSEN1, p.E318G Variant Increases the Risk of Alzheimer's Disease in APOE-ε4 Carriers. PLoS Genet. 2013 Aug;9(8):e1003685. PubMed.
  3. . Novel presenilin 1 variant (P117A) causing Alzheimer's disease in the fourth decade of life. Neurosci Lett. 2008 Jun 20;438(2):257-9. Epub 2008 Apr 15 PubMed.
  4. . Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
  5. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

Other Citations

  1. E318G

External Citations

  1. Kauwe et al., 2008

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Ataxic variant of Alzheimer's disease caused by Pro117Ala PSEN1 mutation. J Neurol Neurosurg Psychiatry. 2007 Dec;78(12):1414-5. PubMed.

Other mutations at this position


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