Mutations

PSEN1 M146I (G>C)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73640373 G>C
dbSNP ID: rs63750391
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ATG to ATC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was found in a Swedish family with six cases of documented dementia across four consecutive generations. The family was first described in 1946 (Essen-Möller, 1946) and followed up with genetic analysis 50 years later (Gustafson et al., 1998).

All six affected cases showed typical symptoms of AD. Myoclonic twitching, the language disorder palilalia, and major motor seizures were also reported. In addition, psychomotor slowness, increased muscular tension, a stiff, stooped gait, and a rapid loss of weight were observed. Cognitive decline started between 35 and 49 years of age.

Neuropathology
Neuropathology was typical of AD in three cases, but unusually severe, with a pronounced involvement of central gray structures, including the claustrum, the nuclei around the third ventricle, the central thalamic nuclei, and the brain stem. There were no vascular lesions and amyloid angiopathy was very mild.

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.

M146 is the site of several AD-related mutations and is fully conserved in most animal presenilins. It is a semi-conservative substitution (hydrophobic amino acid) in an α-helix of a transmembrane domain. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that this residue 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

An iPSC line derived from skin fibroblasts of a 46-year-old symptomatic man carrying the mutation has been generated (Li et al., 2016). Moore and colleagues also created an iPSC line with the M146I mutation (nucleotide change unspecificed) (Moore et al, 2015). In addition, a transgenic minipig carrying the APP Swedish mutation and the PSEN1 M146I mutation has been generated (Jakobsen et al., 2016).

Last Updated: 22 Aug 2019

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References

News Citations

  1. Familial Alzheimer’s Mutations: Different Mechanisms, Same End Result
  2. CryoEM γ-Secretase Structures Nail APP, Notch Binding

Paper Citations

  1. . Generation of induced pluripotent stem cells (iPSCs) from an Alzheimer's disease patient carrying a M146I mutation in PSEN1. Stem Cell Res. 2016 Mar;16(2):334-7. Epub 2016 Jan 14 PubMed.
  2. . APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 2015 May 5;11(5):689-96. Epub 2015 Apr 23 PubMed.
  3. . 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.
  4. . A Family with Alzheimer's Disease. Acta Psychiatrica Scandinavica, September 1946
  5. . A 50-year perspective of a family with chromosome-14-linked Alzheimer's disease. Hum Genet. 1998 Mar;102(3):253-7. PubMed.
  6. . Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry. 2019 Apr 12; PubMed.
  7. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  8. . 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.

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.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A 50-year perspective of a family with chromosome-14-linked Alzheimer's disease. Hum Genet. 1998 Mar;102(3):253-7. PubMed.

Other mutations at this position

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