Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640373 G>A
dbSNP ID: rs63750391
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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. Three carriers were also reported in a subsequent study of a Taiwanese cohort of patients with early onset dementia (Hsu et al., 2021).

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. A subsequent study, including two British families, found that two of three carriers (nucleotide change unspecified) had myoclonus and seizures, one had spastic paraperesis, and one had extrapyramidal signs (Ryan et al., 2016).

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

Neuropathology

Autopsies from four Danish individuals revealed neuropathology consistent with AD (Jørgensen et al., 1996). Assessment of Aβ deposition in different cortical layers of a British 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.

In three Taiwanese carriers, plasma levels of tau were increased, while Aβ42 and Aβ40 levels were decreased (Hsu et al., 2021).

Biological Effect

This mutation has been implicated in several damaging effects. 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 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 indicated 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).

In addition, the variant may affect another γ-secretase substrate, the developmental regulator Notch. Premature neurogenesis was observed during the differentiation of induced pluripotent stem cells harboring the mutation in a 2D model of cortical differentiation, as well as in the generation of a 3D cerebral organoid (Arber et al., 2021).

Moreover, as assessed in cortical neurons derived from patient induced pluripotent stem cells (iPSCs), M146I disrupted 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). This mutation has also been reported to cause a harmful response to inflammation. When patient iPSCs were chronically exposed to tumor necrosis factor, a proinflammatory cytokine, they secreted toxic Aβ and α-synuclein aggregates (Whiten et al., 2020).

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).

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. M146I (G>A): 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>A): 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.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. M146I (G>A): At least one family with >=3 affected carriers and >=1 unaffected noncarriers.

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.
Jørgensen P, Bus C, Pallisgaard N, Bryder M, Jørgensen AL. Familial Alzheimer's disease co-segregates with a Met146I1e substitution in presenilin-1. Clin Genet. 1996 Nov;50(5):281-6. PubMed.
Lin YS, Cheng CY, Liao YC, Hong CJ, Fuh JL. 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.
Hsu JL, Lin CH, Chen PL, Lin KJ, Chen TF. Genetic study of young-onset dementia using targeted gene panel sequencing in Taiwan. Am J Med Genet B Neuropsychiatr Genet. 2021 Mar;186(2):67-76. Epub 2021 Feb 13 PubMed.
Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 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.
Arber C, Lovejoy C, Harris L, Willumsen N, Alatza A, Casey JM, Lines G, Kerins C, Mueller AK, Zetterberg H, Hardy J, Ryan NS, Fox NC, Lashley T, Wray S. Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis. Cell Rep. 2021 Jan 12;34(2):108615. 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.
Whiten DR, Brownjohn PW, Moore S, De S, Strano A, Zuo Y, Haneklaus M, Klenerman D, Livesey FJ. Tumour necrosis factor induces increased production of extracellular amyloid-β- and α-synuclein-containing aggregates by human Alzheimer's disease neurons. Brain Commun. 2020;2(2):fcaa146. Epub 2020 Sep 15 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>A)

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