Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73186867 G>C
Position: (GRCh37/hg19):Chr14:73653575 G>C
dbSNP ID: rs63751484
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TGG to TGC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was initially detected in a French kindred (Alz 064) reported to have three individuals affected by AD, spanning three generations (Campion et al., 1999). Age at onset ranged from 37 to 47 years. The proband was homozygous for the APOE3 allele.

The variant was also found in a Chinese man with a family history of AD and age at onset of 47 years (Mao et al., 2021). His APOE genotype was E2/E3.

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

Neuropathology

Neuropathological data are unavailable.

Biological Effect

Experiments in transfected cells revealed W165C (nucleotide change unspecified) increased the Aβ42/40 ratio and decreased the Aβ37/40 ratio, both being predictive of AD, with the latter outperforming the former (Liu et al., 2022, Apr 2022 news).

Cryo-electron microscopy studies of the atomic structure of γ-secretase bound to APP fragments indicate that, in wild-type PSEN1, W165 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); its hydroxyl group forming H-bonds with the substrate (Odorčić et al., 2024; Guo et al., 2024; Jun 2024 news). Also, substitution of tryptophan with cysteine, a smaller hydrophilic residue, is expected to reduce the strength of the PSEN1-APP hydrophobic interaction (Guo et al., 2024). Molecular dynamics simulations have implicated W165 in the formation of an internal docking site that stabilizes substrate binding (Chen and Zacharias, 2022), and 3D modeling of a synonymous substitution, W165C (G>T), suggested it induces significant conformational changes (Van Giau et al., 2019). Three in silico algorithms (SIFT, Polyphen2, and LRT) predicted W165C is deleterious (Mao 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. W165C (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.

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: 01 Jul 2024

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References

News Citations

Mutations Citations

Paper Citations

Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
Mao C, Li J, Dong L, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Román GC, Cui L, Gao J. Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 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.
Odorčić I, Hamed MB, Lismont S, Chávez-Gutiérrez L, Efremov RG. Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform. Nat Commun. 2024 May 27;15(1):4479. PubMed.
Guo X, Li H, Yan C, Lei J, Zhou R, Shi Y. Molecular mechanism of substrate recognition and cleavage by human γ-secretase. Science. 2024 Jun 7;384(6700):1091-1095. Epub 2024 Jun 6 PubMed.
Chen SY, Zacharias M. An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations. Biophys J. 2022 Jun 21;121(12):2330-2344. Epub 2022 May 20 PubMed.
Van Giau V, Pyun JM, Suh J, Bagyinszky E, An SS, Kim SY. A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer's disease. BMC Neurol. 2019 Aug 7;19(1):188. PubMed.

Mutations

PSEN1 W165C (G>C)

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