Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653575 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TGG to TGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was first identified in a whole-exome sequencing search for genetic variants associated with AD in 17 individuals from India with advanced AD. All patients had one or more first-degree relatives diagnosed with dementia. The search was focused on coding regions previously implicated in dementia (Syama et al., 2018). Affected patients developed disease in their 40s, with rapid progression. (The mutation is also referred to as W161C in this study as it maps to amino acid 161 in the 463-amino acid PSEN1 isoform).

The mutation was subsequently found in a Korean man and a Chinese Han woman. The Korean man had a family history of early onset AD (Van Giau et al., 2019). At age 50, he presented with memory loss, as well as temporal and spatial disorientation. His deceased mother had suffered from AD with onset in her 50s, and his deceased brother experienced AD onset in his 40s. He had an APOE2/3 genotype. The Chinese woman developed progressive memory loss starting at age 48 (Han et al. 2020). By age 53, she had emotional instability, difficulties with language, and slowed movements. Her father, who died at age 55, experienced similar symptoms.

The mutation was absent from the Korean Reference Genome Database, as well as from the gnomAD, ExAC, and 1000 genomes databases (Van Giau et al., 2019).

Neuropathology
Although no autopsy observations were reported for this mutation, MRI showed diffuse cerebral and cerebellar atrophy in one patient (Syama et al., 2018), global brain atrophy without vascular lesions in another (Han et al., 2020), and mild, bilateral atrophy of the hippocampus and bilateral lobe, three years after symptom onset, in a third patient (Van Giau et al., 2019). Moreover, in the latter patient, FBB-PET at five years after symptom onset showed increased amyloid deposition in the parietal, frontal, and temporal lobes, as well as in the precuneus.

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).

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 (Syama et al., 2018; Van Giau et al., 2019; Han et al., 2020; Xiao et al., 2021). In addition, three-dimensional modeling programs suggested the mutation induces significant conformational changes, disrupting several hydrogen bonds with other amino acids and creating new interactions (Van Giau et al., 2019).

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-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. W165C (G>T): The variant was reported in 3 or more unrelated patients with the same phenotype, and absent from controls.

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>T): 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: 13 Jun 2024

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References

News Citations

Paper Citations

Syama A, Sen S, Kota LN, Viswanath B, Purushottam M, Varghese M, Jain S, Panicker MM, Mukherjee O. Mutation burden profile in familial Alzheimer's disease cases from India. Neurobiol Aging. 2018 Apr;64:158.e7-158.e13. Epub 2017 Dec 12 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.
Han LH, Xue YY, Zheng YC, Li XY, Lin RR, Wu ZY, Tao QQ. Genetic Analysis of Chinese Patients with Early-Onset Dementia Using Next-Generation Sequencing. Clin Interv Aging. 2020;15:1831-1839. Epub 2020 Oct 2 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.
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 W165C (G>T)

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