Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173665 G>C
Position: (GRCh37/hg19):Chr14:73640373 G>C
dbSNP ID: rs63750391
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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.

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

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 (Gustafson et al., 1998). There were no vascular lesions and amyloid angiopathy was very mild.

Of note, assessment of Aβ deposition in different cortical layers of a British M146I carrier (nucleotide change unspecified) 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 (nucleotide change unspecified) carrier 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.

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).

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).

Pathogenicity

Alzheimer's Disease : Pathogenic

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>C): 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

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References

News 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.
Essen‐Moeller E. A Family with Alzheimer's Disease. Acta Psychiatrica Scandinavica, September 1946
Gustafson L, Brun A, Englund E, Hagnell O, Nilsson K, Stensmyr M, Ohlin AK, Abrahamson M. A 50-year perspective of a family with chromosome-14-linked Alzheimer's disease. Hum Genet. 1998 Mar;102(3):253-7. 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>C)

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