Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637661 G>C
dbSNP ID: rs63749967
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTG to CTG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was originally identified in a French family referred to as SAL 508. The three affected individuals, across three generations, presented with early-onset Alzheimer’s disease (AD) with onset ranging from 53 to 58 years of age. Co-segregation between the muation and AD could not be demonstrated (Campion et al., 1995). This mutation was reported in 1995, the same year that the presenilin-1 gene was cloned (Sherrington et al., 1995). The variant is absent from the gnomAD variant database (May 2021).

Neuropathology

Unknown.

Biological Effect

In CHO and HEK-293 cells expressing APP695, the mutation resulted in a slightly lower ratio of secreted Aβ42/Aβ40 (Shioi et al., 2007). In an in vitro assay using purified proteins to test the mutant's ability to cleave the APP-C99 substrate, however, the Aβ42/Aβ40 ratio was similar to that produced by wild-type PSEN1.  Production of both Aβ42 and Aβ40 was reduced (Sun et al., 2017).

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicated this variant is damaging (Xiao et al., 2021).

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References

Paper Citations

1. Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S. Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
2. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754-60. PubMed.
3. Shioi J, Georgakopoulos A, Mehta P, Kouchi Z, Litterst CM, Baki L, Robakis NK. FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem. 2007 May;101(3):674-81. Epub 2007 Jan 24 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. 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. gnomAD variant database

Further Reading