Mutations

PSEN1 R377M

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
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.

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).

Last Updated: 09 Aug 2019

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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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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

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