Mutations

PSEN1 G217D

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease, Parkinsonism
Position: (GRCh38/hg38):Chr14:73192745 G>A
Position: (GRCh37/hg19):Chr14:73659453 G>A
dbSNP ID: rs63750444
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGT to GAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation was found in a family of Japanese origin with five individuals, spanning two generations, afflicted by early onset dementia and motor impairments (Takao et al., 2002). Two siblings had dementia and parkinsonism with impaired gait, stooped posture, rigidity, and bradykinesia. The proband was 42 years old and his sister in her late 30s at age of onset. Only the sister was genotyped and found to be a carrier of the mutation.

This variant was also reported in a French sporadic case of AD with onset at age 50 and disease duration of five years (Lanoiselée et al., 2017).

The variant was absent from 30 Caucasians and 30 unrelated Japanese controls (Takao et al., 2002), as well as from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology
In two cases examined, neuropathology included numerous cotton wool plaques, neuritic plaques, severe amyloid angiopathy, neurofibrillary tangles, neuronal loss, and gliosis (Takao et al., 2002). Cotton wool plaques, Aβ42-positive and containing mostly neuropil elements and extracellular amyloid fibrils, were found in the cortex, caudate nucleus, putamen, claustrum, thalamus, substantia innominate, and colliculi. The authors hypothesize that the abundance of these plaques in the striatum may underlie the parkinsonian syndrome observed in the patients.

MRI and CT scans of the proband’s sister’s brain showed severe atrophy of the frontal and temporal regions and mild atrophy of the cerebellum. In this same patient, SPECT revealed hypoperfusion of the frontal, temporal, and parietal regions.

Biological Effect

A study that examined a range of Aβ peptides produced by human embryonic kidney cells expressing this mutant and lacking endogenous PSEN1 and PSEN2 revealed increased Aβ42/Aβ40 and decreased Aβ37/Aβ42, both indicators of reduced Aβ trimming activity (Liu et al., 2022; Apr 2022 news). Of note, in this study, Aβ37/Aβ42 outperformed Aβ42/Aβ40 as a biomarker for distinguishing between control and AD samples. This variant also increased production of Aβ43.

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 : Likely 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.

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)

Research Models

Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 50 year-old AD patient (Auboyer et al., 2019).

Last Updated: 15 Nov 2022

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. Auboyer L, Monzo C, Wallon D, Rovelet-Lecrux A, Gabelle A, Gazagne I, Cacheux V, Lehmann S, Crozet C. Generation of induced pluripotent stem cells (IRMBi001-A) from an Alzheimer's disease patient carrying a G217D mutation in the PSEN1 gene. Stem Cell Res. 2019 Jan;34:101381. Epub 2019 Jan 3 PubMed.
  2. Takao M, Ghetti B, Hayakawa I, Ikeda E, Fukuuchi Y, Miravalle L, Piccardo P, Murrell JR, Glazier BS, Koto A. A novel mutation (G217D) in the Presenilin 1 gene ( PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum. Acta Neuropathol. 2002 Aug;104(2):155-70. PubMed.
  3. Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
  4. 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.
  5. 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.

External Citations

  1. gnomAD v2.1.1

Further Reading

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Protein Diagram

Primary Papers

  1. Miravalle L, Murrell JR, Takao M, Glazier B, Piccardo P, Vidal R, Ghetti B. Genetic mutations associated with presenile dementia. Neurobiol Aging. 2002 Jul-Aug; 23(S1):322.
  2. Takao M, Ghetti B, Hayakawa I, Ikeda E, Fukuuchi Y, Miravalle L, Piccardo P, Murrell JR, Glazier BS, Koto A. A novel mutation (G217D) in the Presenilin 1 gene ( PSEN1) in a Japanese family: presenile dementia and parkinsonism are associated with cotton wool plaques in the cortex and striatum. Acta Neuropathol. 2002 Aug;104(2):155-70. PubMed.

Other mutations at this position

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