Mutations

PSEN1 V94M

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73637697 G>A
dbSNP ID: rs63750831
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTG to ATG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was identified in a single patient from Colombia diagnosed with probable Alzheimer’s disease according to NINCDS-ADRDA criteria. The patient, known as patient 189, experienced symptom onset at age 53, but had no family history of dementia. Mutation segregation with the disease could not be determined, as DNA from family members was unavailable. The reporting authors suspected pathogenicity based on the conservation of the amino acid in other species and the absence of the mutation in 53 control subjects (Arango et al., 2001). However, in a subsequent study, the variant was described as most likely having reduced penetrance based on its allele count (two) and frequency (0.0008 percent) in the gnomAD variant database (Koriath et al., 2018).

Neuropathology

Unknown.

Biological Effect

An in vitro assay using purified proteins to test the ability of the variant to cleave the APP-C99 substrate revealed decreased Aβ42 and Aβ40 production, but the Aβ42/Aβ40 ratio was similar to that generated by wild-type PSEN1 (Sun et al. 2017).

Last Updated: 16 Jul 2019

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References

Paper Citations

  1. . Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet. 2001 Oct 1;103(2):138-43. PubMed.
  2. . Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; 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.

Further Reading

Papers

  1. . Presenilin mutations in a Colombian familial and sporadic AD sample. Neurobiol Aging. 2000 May-Jun;;21(Supp 1):176

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia. Am J Med Genet. 2001 Oct 1;103(2):138-43. PubMed.

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