Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640327 A>G
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAC to CGC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5


This mutation was detected in a Japanese woman with apparently sporadic early onset Alzheimer's disease; no other individual in her family was known to have dementia. Cognitive impairment began at age 45 and she met NINCDS-ADRDA criteria for AD (Ikeda et al., 2013). In addition to dementia, the patient suffered from a persecution complex and developed epilepsy at age 52. This variant was absent from the EVS and ExAC variant databases (Hsu et al., 2020).


Neuropathology data are unavailable, but brain imaging performed six years after disease onset showed atrophy and reduced blood flow in the parietal and temporal lobes.

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased production of Aβ40 and Aβ42, and a slight increase in the Aβ42/Aβ40 ratio (Sun et al., 2017). However, in mouse neuroblastoma cells, secretion of both Aβ40 and Aβ42 were reported as increased, with an approximately twofold elevation of the Aβ42/Aβ40 ratio (Hsu et al., 2020). 

Also of note, H131 has been suggested to act as a pH sensor that may be relevant to normal APP processing in the acidic lumens of late endosomes and lysosomes (Cai et al., 2019). Substitution of this residue with one of several polar amino acids, including arginine, resulted in an increased Aβ42/Aβ42+Aβ40 ratio in a cell-free assay. It also eliminated the sensitivity of PSEN1 to pH. At ph 6.5, Aβ production by wild-type PSEN1 resulted in increased Aβ42/Aβ42+Aβ40 compared with production at neutral pH, while the ratios generated by the H463R mutant were similar to the acidic wild-type ratio, regardless of pH. 

H131 is not conserved between PSEN1 and PSEN2 (Hsu et al., 2020). In silico analyses predicted the H131R substitution to be benign by Polyphen, but damaging by SIFT. Based on their classification scheme, Hsu et al. described this variant as probably pathogenic.

Last Updated: 26 Feb 2020


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Paper Citations

  1. . Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. Amyloid. 2013 Jun;20(2):107-12. PubMed.
  2. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  3. . 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.
  4. . Histidine 131 in presenilin 1 is the pH-sensitive residue that causes the increase in Aβ42 level in acidic pH. J Biochem. 2020 May 1;167(5):463-471. PubMed.

Further Reading

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. . Cerebrospinal fluid levels of phosphorylated tau and Aβ1-38/Aβ1-40/Aβ1-42 in Alzheimer's disease with PS1 mutations. Amyloid. 2013 Jun;20(2):107-12. PubMed.


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