Mutations

PSEN1 D40del (delACG)

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73637533 ACG>---
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: ACG to ---
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This variant is a trinucleotide deletion within exon 4 of PSEN1. The consequence of this deletion is the absence of one amino acid (D) from the presenilin-1 protein sequence. The reading frame remains intact. This deletion was detected by whole-exome sequencing in one of 424 French people with early onset AD This individual had apparently sporadic AD with onset at age 52. APOE genotype was E3/E4 (Nicolas et al., 2015).

In a subsequent study, the D40 deletion was described as "most likely benign" or causing an "only small increase in risk" based on its allele count (39) and frequency (0.0138 percent) in the gnomAD variant database (Koriath et al., 2018). The penetrance was calculated to be two percent or less.

Neuropathology

Unknown.

Biological Effect

An in vitro assay using purified proteins to test the ability of PSEN1 with a D40 deletion to cleave the APP-C99 substrate revealed a robust decrease in Aβ42 production, and undetectable levels of Aβ40 (Sun et al. 2017). However, the deletion does not cause a frame shift and a similar deletion, also resulting in loss of D40, was predicted not to be pathogenic by the Protein Variation Effect Analyzer (PROVEAN) algorithm (Nygaard et al., 2014).

Last Updated: 16 Jul 2019

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References

Paper Citations

  1. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; 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.
  4. . A Novel Presenilin 1 Mutation in Early-Onset Alzheimer's Disease With Prominent Frontal Features. Am J Alzheimers Dis Other Demen. 2014 Jan 24;29(5):433-435. PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.

Other mutations at this position

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