Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173619 A>G
Position: (GRCh37/hg19):Chr14:73640327 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAC to CGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was first 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. 

The mutation was subsequently reported in a Chinese Han female in Taiwan who had impaired memory, topographic disorientation, and headaches starting at age 49 (Lin et al., 2020). Her elderly sister had amnesia starting at age 52, and her father died at age 65.

This variant was absent from the EVS and ExAC variant databases (Hsu et al., 2020).

Neuropathology

Neuropathology data are unavailable, but PiB-PET brain imaging of the Chinese Han patient at age 62 demonstrated extensive cortical and striatal amyloid deposition, and FDG-PET showed hypometabolism in the precuneus and bilateral temporo-parietal regions (Lin et al., 2020). Also, an MRI scan at age 61 showed mild medial-temporal and parietal atrophy. In addition, in the Japanese patient, brain imaging performed six years after disease onset showed atrophy and reduced blood flow in the parietal and temporal lobes (Ikeda et al., 2013).

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. 

Although H131 is not conserved between PSEN1 and PSEN2, and in silico analyses yielded conflicting predictions (Hsu et al., 2020; Lin et al., 2020, Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021). Both Hsu et al. and Lin et al. classified this variant as probably pathogenic.

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Paper Citations

1. Ikeda M, Yonemura K, Kakuda S, Tashiro Y, Fujita Y, Takai E, Hashimoto Y, Makioka K, Furuta N, Ishiguro K, Maruki R, Yoshida J, Miyaguchi O, Tsukie T, Kuwano R, Yamazaki T, Yamaguchi H, Amari M, Takatama M, Harigaya Y, Okamoto K. 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. Lin YS, Cheng CY, Liao YC, Hong CJ, Fuh JL. Mutational analysis in familial Alzheimer's disease of Han Chinese in Taiwan with a predominant mutation PSEN1 p.Met146Ile. Sci Rep. 2020 Nov 13;10(1):19769. PubMed.
3. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
4. Sun L, Zhou R, Yang G, Shi Y. 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.
5. Cai T, Hatano A, Kanatsu K, Tomita T. 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.
6. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

1. CADD v.1.6

Further Reading

Learn More

1. Japanese Familial Alzheimer's Disease Database