Mutations

PSEN1 I168T

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653583 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATA to ACA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This variant was found in an exome sequencing study of 141 individuals with late-onset Alzheimer’s disease and 179 elderly controls who did not have evidence of neuropathology at the time of their deaths. The mutation carrier was a Caucasian man who was diagnosed with AD at the age of 86. His APOE genotype was ε2/ε4. He died at age 94 with extensive neuropathology (Braak stage V). He had no known family history of dementia (Sassi et al., 2014).

Neuropathology

The individual carrying this variant was found to have severe neuropathology consistent with AD (Braak V) (Sassi et al., 2014).

Biological Effect

In an in vitro assay with isolated proteins, this mutant produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). In silico, this variant is predicted to be possibly damaging. It has been classified as probably pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Sassi et al., 2014).

Last Updated: 22 Sep 2019

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References

Paper Citations

  1. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-6. Epub 2014 Jun 16 PubMed.
  2. . 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.
  3. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-6. Epub 2014 Jun 16 PubMed.

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