Mutations

PSEN1 M146I (G>T)

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
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 synonymous variants M146I (G>A) and M146I (G>C) which have been classified as pathogenic. 

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Neuropatholgoical data are unavailable, but carriers of different mutations resulting in the same amino acid substitution (M146I (G>A) and M146I (G>C)) had neuropathology consistent with AD. Moreover, assessment of Aβ deposition in different cortical layers of one M146I carrier (nucleotide change unknown) showed robust Aβ accumulation in layer 3, with very few deposits in deeper layers (Willumsen et al., 2021). In this same patient, cerebral amyloid angiopathy was observed in the frontal cortex and α-synuclein deposits in the amygdala.

Assessment of Aβ deposition in different cortical layers of one M146I carrier (nucleotide change unknown) showed robust Aβ accumulation in layer 3, with very few deposits in deeper layers (Willumsen et al., 2021). In this same patient, cerebral amyloid angiopathy was observed in the frontal cortex and α-synuclein deposits in the amygdala.

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).

Also, in one M146I carrier (nucleotide change unspecified) with an APOE3/3 genotype, blood ApoE levels were reduced compared with those of non-carriers (Islam et al., 2022). This may be due to the disruption of PSEN1’s proposed role in ApoE secretion.

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021). The position is fully conserved in most animal presenilins.

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).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled several pathogenic ACMG-AMP criteria, and a synonymous variant, resulting in the same amino acid substitution, is pathogenic. However, it was not classified by Alzforum, because only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS1-S

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. M146I (G>T): Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 22 Feb 2022

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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. . Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease. Brain Pathol. 2021 Jul 28;:e13009. PubMed.
  3. . Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry. 2019 Apr 12; PubMed.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  5. . 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.
  6. . Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis. J Neurosci. 2022 Feb 23;42(8):1574-1586. Epub 2022 Jan 5 PubMed.
  7. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
  8. . APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 2015 May 5;11(5):689-96. Epub 2015 Apr 23 PubMed.

External Citations

  1. gnomAD v2.1.1

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.

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

Alzpedia

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