Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73198057 G>A
Position: (GRCh37/hg19):Chr14:73664765 G>A
dbSNP ID: rs121917807
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGT to AGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This mutation was found in a family of Japanese origin with six affected individuals spanning two generations (Matsubara-Tsutsui et al., 2002). The initial symptoms were spastic paraparesis and apraxia followed by dementia, with a mean age of onset of 45 years. The mutation was detected in the proband, but not in three unaffected family members who were past the mean age of onset, nor in 200 healthy controls nor 200 sporadic AD patients. Morevoer, it was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
An autopsy of a 52-year-old mutation carrier revealed neuropathology consistent with AD, including marked atrophy of the temporal and frontal lobes. In addition, numerous cotton-wool plaques were found in the cerebral cortex with accompanying cerebral amyloid angiopathy. Also, widespread neurofibrillary tangles were observed, as well as reactive gliosis in the white matter (Akatsu et al., 2008). MRI in another patient revealed atrophy of the cerebral cortex, particularly of the parietal lobes, and abnormalities in the deep white matter of the frontal lobes and areas surrounding the lateral ventricles (Matsubara-Tsutsui et al., 2002). SPECT showed marked hypoperfusion in parietal and occipital areas, typical of AD.

Biological Effect
An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it generates less Aβ42, and much less Aβ40, than wild-type PSEN1, resulting in an approximately 10-fold elevation of the Aβ42/Aβ40 ratio (Sun et al., 2017).

The amino acid position is conserved across species and related proteins, including mouse PSEN1, human PSEN2, C. elegans Spe-4, and C. elegans Sel-12 (Matsubara-Tsutsui et al., 2002). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates this residue appears to help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news). Moreover, 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). These authors classified the variant as pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

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.

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. G266S: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

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. G266S: 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.

PP1-P

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.

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: 28 Feb 2022

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References

News Citations

Paper Citations

Matsubara-Tsutsui M, Yasuda M, Yamagata H, Nomura T, Taguchi K, Kohara K, Miyoshi K, Miki T. Molecular evidence of presenilin 1 mutation in familial early onset dementia. Am J Med Genet. 2002 Apr 8;114(3):292-8. PubMed.
Akatsu H, Yamagata H, Wake A, Watanabe I, Kimura N, Kamada K, Miyazaki T, Tanabe H, Miki T, Yamamoto T, Hori A, Mimuro M, Yoshida M, Hashizume Y. The first autopsy case report of familial Alzheimer's disease (AD) associated with a mutation at G266S in the presenilin 1 (PSEN1) gene. Alzheimers Dement. 2008 Jul;4(4 Suppl);T578.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 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.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Mutations

PSEN1 G266S

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