Mutations

PSEN1 A246P

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
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 identified in two siblings with Alzheimer’s disease (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.

Neuropathology

Histological examination of the proband’s brain revealed changes typical of AD (Braak and Braak stage VI, CERAD C) as well as cerebral amyloid angiopathy. In addition, some α-synuclein inclusions were observed in the entorhinal cortex.

Biological Effect

Unknown. In silico this mutation has been predicted probably damaging by PolyPhen-2. Moreover, 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).

Last Updated: 13 Aug 2019

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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. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 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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