Mutations

PSEN1 I167del (TATdel)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653582 ATT>---
dbSNP ID: rs63750879
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: ATT.ATA to ATA
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

The mutation was found in a study of British AD patients with a family history of AD with at least one affected first-degree relative, and an age of onset of less than 61 years (Janssen et al., 2003). The age of onset of the proband was 45 years. Five members of the individual’s family, spanning two generations, were diagnosed with AD, with a mean age of onset of 52 years. DNA was unavailable from these relatives, however, so co-segregation of the mutation and disease could not be demonstrated. The mutation was absent from 100 healthy, unrelated white control patients.

Neuropathology
Unknown

Biological Effect
This mutation is a deletion of three nucleotides: the third base pair of codon 167 and the first and second base pairs of codon 168, resulting in the in-frame deletion of isoleucine 167. In an in vitro assay with isolated proteins, a I167del mutant PSEN1 (nucleotide change unspecified) produced less Aβ42 than wild-type PSEN1, and Aβ40 production was undetectable (Sun et al., 2017). This mutation is predicted to be damaging by in silico analysis using SIFT software and definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010.

 

 

Last Updated: 22 Sep 2019

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References

Paper Citations

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. 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

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.

Other mutations at this position

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