Mutations

PSEN1 M139L

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640350 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to TTG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was found in a Chinese family with 11 members affected by early onset AD, spanning three generations (Qiu et al., 2019). The proband began experiencing memory problems at 45 years of age, and her cognition progressively declined over the next two years, with additional symptoms including visuospatial impairment and irritability. By the age of 50, she was nearly bedridden. Three affected family members had similar clinical features with ages of onset ranging from 51 to 56 years.

The mutation was reported to co-segregate with disease, being present in five affected family members, but not in the proband’s only unaffected sibling. It was also absent from 100 cognitively healthy controls and 100 late-onset AD patients. The mutation was not found in three population databases (ExAC, Exome Variant Server, 1000 Genome). The family had no mutations in either the PSEN2 or APP genes. Four of the five affected members carried an APOE4 allele.

Neuropathology
Neuropathology data are unavailable, but MRI in two individuals revealed bilateral atrophy in the hippocampus and cerebral cortex (Qiu et al., 2019).

Biological Effect
In HEK293-APPswe cells expressing PSEN1 M139L, Aβ40 levels were moderately decreased and the Aβ42/Aβ40 ratio was increased approximately 1.6-fold compared with cells expressing wild-type PSEN1 (Qiu et al., 2019). No changes in tau phosphorylation were detected. Computational programs to evaluate potential pathogenicity, PANTHER, Mutation Taster, and PolyPhen-2, predicted the mutation is probably damaging. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue 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. . A Novel PSEN1 M139L Mutation Found in a Chinese Pedigree with Early-Onset Alzheimer's Disease Increases Aβ42/Aβ40 ratio. J Alzheimers Dis. 2019;69(1):199-212. 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

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A Novel PSEN1 M139L Mutation Found in a Chinese Pedigree with Early-Onset Alzheimer's Disease Increases Aβ42/Aβ40 ratio. J Alzheimers Dis. 2019;69(1):199-212. PubMed.

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