Mutations

PSEN1 M146I (G>T)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640373 G>T
dbSNP ID: rs63750391
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to ATT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was found in a screen for mutations in the open reading frame of the PSEN1 gene in participants from the U.S., Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001). The cohort included 372 patients with AD and 42 asymptomatic individuals with a strong family history of AD. Evidence for co-segregation of this mutation with disease is not available. However, it is the site of several AD-related mutations, including M146I (G>A) and M146I (G>C), both of which have been associated with AD neuropathology. The position is fully conserved in most animal presenilins.

Neuropathology
Unknown

Biological Effect
The Aβ peptidome of neurons derived from iPSCs from a presymptomatic M146I (nucleotide change unspecified) mutation carrier revealed increased Aβ42/Aβ40 and Aβ42/Aβ38 ratios compared with controls (Arber et al., 2019; see April 2019 news). In contrast, Aβ38/Aβ40 and Aβ43/Aβ40 ratios remained unchanged. The elevated ratios suggest inefficient carboxypeptidase activity, predisposing neurons to accumulate longer Aβ fragments. Western blot analyses revealed a high degree of variablilty in mutant protein levels, consistent with altered protein stability. 

Last Updated: 18 Apr 2019

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References

Mutations Citations

  1. PSEN1 M146I (G>A)
  2. PSEN1 M146I (G>C)

News Citations

  1. Familial Alzheimer’s Mutations: Different Mechanisms, Same End Result

Paper Citations

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry. 2019 Apr 12; PubMed.

Further Reading

Papers

  1. . Self-Organizing 3D Human Neural Tissue Derived from Induced Pluripotent Stem Cells Recapitulate Alzheimer's Disease Phenotypes. PLoS One. 2016;11(9):e0161969. Epub 2016 Sep 13 PubMed.
  2. . Expression of the Alzheimer's Disease Mutations AβPP695sw and PSEN1M146I in Double-Transgenic Göttingen Minipigs. J Alzheimers Dis. 2016 Jul 14;53(4):1617-30. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.

Other mutations at this position

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