Mutations

PSEN1 R377M

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73683834 G>T
dbSNP ID: rs63751051
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: AGG to ATG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

The mutation was found in a study of British AD patients with a family history of AD with at least one affected first-degree relative, and an age of onset of less than 61 years (Janssen et al., 2003). The age of onset of the proband was 38 years. Two members of the individual’s family, spanning two generations, were diagnosed with AD, with a mean age of onset of 39 years. DNA was unavailable from the affected relatives, however, so co-segregation of the mutation and disease could not be demonstrated. The mutation was absent from 100 healthy, unrelated white control patients, as well as from the gnomAD variant database (gnomAD v2.1.1, Aug 2021).

Neuropathology
Unknown

Biological Effects
Although the biological effects of this mutation are unknown, R377 appears to reside in a location important for γ-secretase cleavage of APP. A cryo-electron microscopy study of the atomic structure of the enzyme bound to an APP fragment indicates the residue forms part of one of two PSEN1 β-strands induced by APP binding. These strands, together with an APP β-strand, form a hybrid, three-stranded β-sheet (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).

Last Updated: 13 Sep 2021

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

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

Paper Citations

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  3. . 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. Aug 2021

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.

Other mutations at this position

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.