Mutations

PSEN1 G111V

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73637749 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGG to GTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was found in a Chinese man with AD who was first diagnosed with mild cognitive impairment at age 55 (Qiu et al., 2019). His memory declined and he developed executive dysfunction during the two years following his initial assessment. His mother first reported memory loss at age 62, and also developed executive dysfunction, as well as visuospatial impairment, with dementia setting in at age 70. The proband’s 64-year-old brother was cognitively healthy. Genetic information was obtained only from the proband, who was homozygous for the APOE 3 allele. The mutation was absent from 100 cognitively normal controls and 100 patients with late-onset AD. It was also absent from several variant databases, including ExAC, Exome Variant Server, 1000 Genomes, ClinVar, and gnomAD.

Neuropathology
Although neuropathological data are unavailable, an MRI of the proband showed bilateral hippocampal atrophy.

Biological Effect
Levels of Aβ40 were reduced in the conditioned media of human embryonic kidney cells expressing APPswe and the mutant PSEN1 protein compared with cells expressing APPswe and wildtype PSEN1. Aβ42 levels were similar in the two cell lines, resulting in an elevated Aβ42/Aβ40 ratio.

In silico algorithms, PANTHER, Mutation Taster, and PolyPhen-2, predicted the mutation is probably damaging. Another mutation at this site, PSEN1 G111W, was also found in an individual with early onset AD and was classified as probably pathogenic.

The authors classified the mutation as “pathogenic” according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (Richards et al., 2015).

Last Updated: 02 Jul 2019

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References

Mutations Citations

  1. PSEN1 G111W

Paper Citations

  1. . Identification of a novel PSEN1 Gly111Val missense mutation in a Chinese pedigree with early-onset Alzheimer's disease. Neurobiol Aging. 2019 May 31; PubMed.
  2. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Identification of a novel PSEN1 Gly111Val missense mutation in a Chinese pedigree with early-onset Alzheimer's disease. Neurobiol Aging. 2019 May 31; PubMed.

Other mutations at this position

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