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 mutation carrier (nucleotide change unspecified) 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. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, M146 closely contacts the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Moreover, as assessed in cortical neurons derived from patient induced pluripotent stem cells, M146I disrupts lysosome function and autophagy, leading to impaired lysosomal proteolysis and defective autophagosome clearance. These effects appear to be caused by accumulation of β-C-terminal fragments of APP (Hung and Livesey, 2018).

Research Models
Induced pluripotent stem cell lines have been created from patient fibroblasts expressing this amino acid substitution (nucleotide change unspecified) (Moore et al., 2015).

Last Updated: 22 Aug 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
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding

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.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  4. . Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer's Disease. Cell Rep. 2018 Dec 26;25(13):3647-3660.e2. PubMed.
  5. . APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 2015 May 5;11(5):689-96. Epub 2015 Apr 23 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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