Mutations

PSEN1 F237L

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659512 T>C
dbSNP ID: rs63750858
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTT to CTT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

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 46 years. Three members of the individual’s family, spanning two generations, were diagnosed with AD, with a mean age of onset of 51 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
The biological effect of this mutation is unknown, but two other mutations at this site are associated with AD. Codon 237 is evolutionarily conserved across human PSEN1, mouse PSEN1, and Caenorhabditis elegans Sel-12 protein, as well as between human PSEN1 and PSEN2 (Sodeyama et al., 2001). Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, the phenylalanine at this position helps form a hydrophobic pocket in the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Last Updated: 01 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. . Very early onset Alzheimer's disease with spastic paraparesis associated with a novel presenilin 1 mutation (Phe237Ile). J Neurol Neurosurg Psychiatry. 2001 Oct;71(4):556-7. PubMed.
  3. . 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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