Mutations

PSEN1 Y154C

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640396 A>G
dbSNP ID: rs63751292
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAT to TGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

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 41 years. Six members of the individual’s family, spanning three generations, were diagnosed with AD. DNA was unavailable from these 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 Effect
Although the biological effects of this mutation are unknown, another mutation at this site, Y154N, has been reported to dramatcially disrupt γ-secretase function. In addition, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, showed that Y154 appears to help stabilize the hybrid β-sheet that forms between PSEN1 and APP in preparation for cleavage (Zhou et al., 2019; Jan 2019).

Last Updated: 06 Aug 2019

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References

Mutations Citations

  1. PSEN1 Y154N

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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