Mutations

PSEN1 A246P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659539 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GCG to CCG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was first reported in two siblings with Alzheimer’s disease in a German study (Roeber et al., 2015). The proband presented at age 47 with memory deficit and social withdrawal. She died at the age of 51 from sepsis. Her brother reportedly had similar symptoms. Their mother and another sibling were also affected by AD, but were not genotyped.

The mutation was also found in a French individual with a family history of AD (Lanoiselée et al., 2017). Age at onset was between 50-51 years, and  disease duration between 1-4 years.

The variant was absent from the ExAC variant database (Lanoiselée et al., 2017).

Neuropathology

Histological examination of the German proband’s brain revealed changes typical of AD (Braak and Braak stage VI, CERAD C) as well as cerebral amyloid angiopathy (Roeber et al., 2015). In addition, some α-synuclein inclusions were observed in the entorhinal cortex. In the French family, levels of Aβ42, tau and phospho-tau in cerebrospinal fluid were consistent with AD (Lanoiselée et al., 2017).

Biological Effect

The biological effect of this mutation is unknown but a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news). Moreover, 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).

This variant has been classified as likely pathogenic (Xiao et al., 2021) using the ACMG-AMP pathogenicity guidelines, and as definitely pathogenic (Lanoiselée et al., 2017) using the Guerreiro pathogenicity guidelines.

Last Updated: 23 Jul 2021

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References

News Citations

  1. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer's disease. J Neural Transm (Vienna). 2015 Dec;122(12):1715-9. Epub 2015 Sep 8 PubMed.
  2. . 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.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  4. . 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.
  5. . 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.
  6. . 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. . Three novel presenilin 1 mutations marking the wide spectrum of age at onset and clinical patterns in familial Alzheimer's disease. J Neural Transm (Vienna). 2015 Dec;122(12):1715-9. Epub 2015 Sep 8 PubMed.

Other mutations at this position

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