Mutations

PSEN1 H214R

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659444 A>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAC to CGC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a Chinese family including nine members spanning two generations affected by early onset dementia (Li et al., 2019). The proband presented with memory decline, mood alterations, and behavioral changes at 41 years of age. His mother, three siblings of his mother, and three of his siblings developed similar symptoms at approximately 40 years of age.

In addition to the proband, the proband’s mother, a sibling, and an uncle were identified as carriers of the mutation. The mutation was absent from 200 Chinese healthy controls and two genetic variant databases (ExAC and 1000 Genomes).

Neuropathology
Although neuropathological data are unavailable, a brain MRI showed mild white matter demyelination of the frontal and parietal lobes, with no apparent atrophy of the cerebral cortex or hippocampus.

Biological Effect
This mutation is predicted to be deleterious based on six different algorithms (Provean, MutPred2, SNAP, Polyphen 2, Mutation Taster, and Mutation Assessor).

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates 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: 26 Aug 2019

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References

News Citations

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

Paper Citations

  1. . Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease. Aging Dis. 2019 Aug;10(4):908-914. 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. . Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease. Aging Dis. 2019 Aug;10(4):908-914. PubMed.

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