Mutations

PSEN1 M146I (G>A)

Overview

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

Findings

This mutation was discovered in a Danish family with a history of AD onset in the mid-40s (Jørgensen et al., 1996).  Two patients tested carried the mutation, while two unaffected, elderly members did not, nor did two unrelated spouses. Moreover, DNA purified from brain tissue obtained at autopsy confirmed the presence of the mutation in two affected members of the previous generation.

Interestingly, the mutation was later detected at a high frequency in a group of 77 Han Chinese patients living in Taiwan with a family history suggestive of autosomal dominant AD (Lin et al., 2020). Sixteen of the 77 patients had a mutation in the PSEN1 gene and, of those, nine carried the M146I (G>A) variant. Carriers showed typical memory impairment with a mean age at onset of 44.7 years, and had other neurological symptoms, including seizures (2 individuals), myoclonic jerks (3 individuals), extrapyramidal symptoms (1 individual), and emotional liability (1 individual). Six of the carriers had a very strong family history of AD. No family relationship between the nine carriers could be gleaned from their self-reported pedigrees. Two large pedigrees were examined. One included 10 subjects with clinically diagnosed or suspected AD, three premature deaths, and 21 individuals with genetically confirmed mutations within the youngest two generations. The other family also included 10 subjects with clinically diagnosed or suspected AD, and eight subjects with genetically confirmed mutations. Both families had at least three affected people in two generations, with one person being a first-degree relative of the other two. 

The mutation was also found in a study of British AD patients with at least one affected first-degree relative, and an age of onset of less than 61 years (Janssen et al., 2003). The family of the proband with this mutation had three affected members spanning two generations, with a mean age at onset of 49 years.

Neuropathology
Autopsies from four individuals revealed neuropathology consistent with AD.

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 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 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). In addition, a double-transgenic Gõttingen minipig was produced carrying one copy of human PSEN1 cDNA with the M146I mutation and three copies of human APP695 cDNA with the Swedish double mutation (Jakobsen et al., 2016).

Last Updated: 17 Nov 2020

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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. . APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 2015 May 5;11(5):689-96. Epub 2015 Apr 23 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.
  3. . Familial Alzheimer's disease co-segregates with a Met146I1e substitution in presenilin-1. Clin Genet. 1996 Nov;50(5):281-6. PubMed.
  4. . Mutational analysis in familial Alzheimer's disease of Han Chinese in Taiwan with a predominant mutation PSEN1 p.Met146Ile. Sci Rep. 2020 Nov 13;10(1):19769. PubMed.
  5. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. 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.
  2. . Genetic testing in familial AD and FTD: mutation and phenotype spectrum in a Danish cohort. Clin Genet. 2009 Aug;76(2):205-9. Epub 2009 Jul 29 PubMed.

Protein Diagram

Primary Papers

  1. . Familial Alzheimer's disease co-segregates with a Met146I1e substitution in presenilin-1. Clin Genet. 1996 Nov;50(5):281-6. PubMed.

Other mutations at this position

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