Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173665 G>T
Position: (GRCh37/hg19):Chr14:73640373 G>T
dbSNP ID: rs63750391
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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 (CAA) was observed in the frontal cortex and α-synuclein deposits in the amygdala. A subsequent study, likely of the same carrier, revealed intense Aβ42 deposition in the temporal and occipital cortices, with Aβ40 pathology in CAA and cortical deposits (Willumsen et al., 2022). Aβ43 deposition was extremely low.

Biological Effect

The Aβ peptidome of neurons derived from iPSCs from a presymptomatic M146I carrier (nucleotide change unspecified) revealed increased Aβ42/Aβ40 and Aβ42/Aβ38 ratios compared with controls (Arber et al., 2019; April 2019 news, Willumsen et al., 2022). In contrast, Aβ38/Aβ40 and Aβ43/Aβ40 ratios remained unchanged, and PSEN1 maturation was unaffected. The elevated ratios suggest inefficient carboxypeptidase activity, predisposing neurons to accumulate longer Aβ fragments. In addition, western blot analyses revealed a high degree of variabililty 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.

M146 is the site of several AD-related mutations and is fully conserved in most animal presenilins. M146I is a semi-conservative substitution (hydrophobic amino acid) in an α-helix of a transmembrane domain. 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.

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. M146I (G>T): Data from M146I, nucleotide change unspecified.

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)

Research Models

Cell and animal research models carrying the M146I substitution (nucleotide change unspecified) have been generated. Induced pluripotent stem cell lines have been created from patient fibroblasts (Moore et al., 2015). Interestingly, neuronal cell models have also been generated directly from adult fibroblasts (Sun et al., 2023, Jun 2023 news). Unlike neurons differentiated from induced pluripotent stem cells, these transdifferentiated neurons, called tNeurons, retain epigenetic marks of aging.

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: 18 Oct 2023

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

Mutations Citations

Paper Citations

Moore S, Evans LD, Andersson T, Portelius E, Smith J, Dias TB, Saurat N, McGlade A, Kirwan P, Blennow K, Hardy J, Zetterberg H, Livesey FJ. APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 2015 May 5;11(5):689-96. Epub 2015 Apr 23 PubMed.
Sun Z, Kwon J-S, Ren Y, Chen S, Cates K, Lu X, Walker CK, Karahan H, Sviben S, Fitzpatrick JA, Valdez C, Houlden H, Karch CM, Bateman RJ, Sato C, Mennerick SJ, Diamond MI, Kim J, Tanzi RE, Holtzman DM, Yoo AS. Endogenous recapitulation of Alzheimers disease neuropathology through human 3D direct neuronal reprogramming. 2023 May 25 10.1101/2023.05.24.542155 (version 1) bioRxiv.
Jakobsen JE, Johansen MG, Schmidt M, Liu Y, Li R, Callesen H, Melnikova M, Habekost M, Matrone C, Bouter Y, Bayer TA, Nielsen AL, Duthie M, Fraser PE, Holm IE, Jørgensen AL. 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.
Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
Willumsen N, Poole T, Nicholas JM, Fox NC, Ryan NS, Lashley T. Variability in the type and layer distribution of cortical Aβ pathology in familial Alzheimer's disease. Brain Pathol. 2022 May;32(3):e13009. Epub 2021 Jul 28 PubMed.
Willumsen N, Arber C, Lovejoy C, Toombs J, Alatza A, Weston PS, Chávez-Gutiérrez L, Hardy J, Zetterberg H, Fox NC, Ryan NS, Lashley T, Wray S. The PSEN1 E280G mutation leads to increased amyloid-β43 production in induced pluripotent stem cell neurons and deposition in brain tissue. Brain Commun. 2023;5(1):fcac321. Epub 2022 Dec 7 PubMed.
Arber C, Toombs J, Lovejoy C, Ryan NS, Paterson RW, Willumsen N, Gkanatsiou E, Portelius E, Blennow K, Heslegrave A, Schott JM, Hardy J, Lashley T, Fox NC, Zetterberg H, Wray S. Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry. 2020 Nov;25(11):2919-2931. Epub 2019 Apr 12 PubMed.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Hung CO, Livesey FJ. 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.
Islam S, Sun Y, Gao Y, Nakamura T, Noorani AA, Li T, Wong PC, Kimura N, Matsubara E, Kasuga K, Ikeuchi T, Tomita T, Zou K, Michikawa M. 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.
Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. 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.

Mutations

PSEN1 M146I (G>T)

Quick Links