Mutations

PSEN1 L418F

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73685847 G>T
dbSNP ID: rs63751316
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTG to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12

Findings

This mutation was found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the United States, Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001). The cohort included 372 patients with AD and 42 asymptomatic individuals with a strong family history of AD. Evidence for co-segregation of this mutation with disease is not available.

The variant was also reported in an American man who suffered from familial AD with  age at onset of 33 years and disease duration of only three years (Leverenz et al., 2006). His APOE genotype was E3/E4.

A subsequent study reported the variant as a de novo mutation in a sporadic case of AD in a French individual (Lanoiselee et al., 2017). Age at onset was 33 years and disease duration was 8 years. The carrier's APOE genotype was E3/E3. 

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology
Lewy body pathology in the amygdala was reported in one individual (Leverenz et al., 2006).

Biological Effect
In an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate, Aβ40 and Aβ42 production were decreased and the Aβ42/Aβ40 ratio was elevated approximately 5-fold (Sun et al., 2017). Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Last Updated: 26 Aug 2021

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006 Mar;63(3):370-6. PubMed.
  3. . APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
  4. . 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.
  5. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.