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). In a subsequent study, a French individual carrying this mutation with symptom onset at age 37 was reported as developing seizures at age 42 (Zarea et al. 2016). 

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: 25 Nov 2019

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. 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. Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
  3. 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

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.