Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640352 G>C
dbSNP ID: rs63750522
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 reported in a Korean family with three affected individuals over two generations (Kim et al., 2010). The proband, a teacher, developed cognitive impairment at age 37. Her clinical presentation was fairly typical for AD and she met NINCDS-ADRDA criteria for probable AD (McKhann et al., 1984). She did not exhibit extrapyramidal symptoms, ataxia, myoclonus, or seizures. Her mother had developed a similar progressive cognitive decline starting in her 30s and died at the age of 45. The proband’s oldest sister developed dementia at age 35. The mutation was detected in the proband and was absent in her three healthy siblings, suggesting that M139I is pathogenic.

Neuropathology

Brain tissue from two cases carrying the M139I mutation was examined by immunohistochemistry (Mathews et al., 2000); however, it was not clear in this report whether the individuals carried the G>A or G>C version. In contrast to the eight other presenilin mutations examined in this study, pyramidal neurons in the two M139I brains showed co-localization of neurofibrillary tangles with presenilin-1 protein. The authors speculated that presenilin may become mislocalized during neurodegeneration. The expression level of presenilin-1 in the M139I cases and endoproteolysis of the protein were comparable to control brains and those with sporadic AD.

Biological Effect

In vitro, the M139I mutation (nucloetide change unspecified) increases the Aβ42/Aβ total ratio in COS-1 cells co-transfected with APP695 (Murayama et al., 1999). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 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. M139I (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)

Last Updated: 22 Feb 2022

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References

News Citations

Paper Citations

Kim HJ, Kim HY, Ki CS, Kim SH. Presenilin 1 gene mutation (M139I) in a patient with an early-onset Alzheimer's disease: clinical characteristics and genetic identification. Neurol Sci. 2010 Dec;31(6):781-3. PubMed.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. PubMed.
Mathews PM, Cataldo AM, Kao BH, Rudnicki AG, Qin X, Yang JL, Jiang Y, Picciano M, Hulette C, Lippa CF, Bird TD, Nochlin D, Walter J, Haass C, Lévesque L, Fraser PE, Andreadis A, Nixon RA. Brain expression of presenilins in sporadic and early-onset, familial Alzheimer's disease. Mol Med. 2000 Oct;6(10):878-91. PubMed.
Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. 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.
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 M139I (G>C)

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