Mutations

PSEN1 M139K

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640351 T>A
dbSNP ID: rs63751106
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to AAG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was reported in a French woman (ALZ 034) with onset of symptoms at age 37. She met NINCDS-ADRDA criteria for probable AD and died at age 47. This may have been a case of a de novo mutation, as the woman had no family history of dementia. Her parents were unaffected at the age of 74 and neither had a family history of dementia. The mutation was absent in the woman’s mother (age 74) and brother (age 50) (Dumanchin et al., 1998).

Neuropathology

Unknown.

Biological Effect

Unknown. Multiple mutations at this position have been reported. Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates M139 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: 13 Aug 2019

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References

News Citations

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

Paper Citations

  1. Dumanchin C, Brice A, Campion D, Hannequin D, Martin C, Moreau V, Agid Y, Martinez M, Clerget-Darpoux F, Frebourg T. De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group. J Med Genet. 1998 Aug;35(8):672-3. PubMed.
  2. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. 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. Dumanchin C, Brice A, Campion D, Hannequin D, Martin C, Moreau V, Agid Y, Martinez M, Clerget-Darpoux F, Frebourg T. De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases. French Alzheimer's Disease Study Group. J Med Genet. 1998 Aug;35(8):672-3. PubMed.

Other mutations at this position

View Table

Alzpedia

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