Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73192712 G>A
Position: (GRCh37/hg19):Chr14:73659420 G>A
dbSNP ID: rs63750082
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 identified in a French pedigree, referred to as ALZ 219, with five individuals affected by early onset Alzheimer’s disease. At least one affected mutation carrier met criteria for probable AD according to NINCDS-ADRDA criteria. Symptom onset in this family clustered at 32 to 34 years of age. The mutation reportedly segregated with disease, although details of the analysis were not described. Note: This mutation was originally reported as G206N (Raux et al., 2005).

An additional family with three affected siblings has been reported. Disease in this family manifested as a rapidly progressing dementia syndrome with features consistent with frontotemporal dementia. The proband developed symptoms at age 39, starting with behavioral changes, depression, and memory and attention deficits. She subsequently developed gait disturbances and bradykinesia. Within a year she had developed seizures and violent behavior. A diagnosis of frontotemporal dementia was suspected, but a biopsy of the frontal cortex revealed neuropathology more consistent with AD. The proband’s sister developed progressive memory impairment at age 37. Like her sister, she developed seizures. The sisters reportedly had a third affected sibling, but clinical details were not available. There was no indication of cognitive impairment in either parent; the father had died at age 60 from liver cancer and the mother died at an unspecified young age. Both siblings carried the mutation. No mutations in APP, PSEN2, or MAPT were detected (Wu et al., 2011).

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

Neuropathology

Biopsy of the frontal cortex showed abundant amyloid and tau deposits consistent with a diagnosis of AD. MRI of one proband showed atrophy of the temporal lobe and mild paraventricular white-matter hyperintensities along with dilation of the third and lateral ventricles. MRI of the proband’s sister showed frontal, parietal, and temporal-lobe atrophy, more prominent on the left. SPECT imaging showed decreased perfusion in the frontotemporal area, again, especially on the left (Wu et al., 2011).

Biological Effect

The G206D mutation was reported to increase Aβ42 production and reduce PSEN1’s interaction with Presenilin enhancer 2 (Pen2), a protein required for activating γ-secretase and exporting PSEN1 from the endoplasmic reticulum (ER) (Chen et al., 2015). It also disrupted ER calcium homeostasis.

A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in G206 could alter the protein's local conformation and affect the positioning of residues that directly contribute to substrate binding (Zhou et al., 2019; Jan 2019 news).

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 : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Research Models

An induced pluripotent stem cell line was created from a male carrier of this mutation (Díaz-Guerra et al., 2019).

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References

News Citations

1. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Díaz-Guerra E, Oria-Muriel MA, Moreno-Jiménez EP, de Rojasb I, Rodríguez C, Rodríguez-Traver E, Orera M, Hernándezb I, Ruizb A, Vicario C. Generation of an integration-free iPSC line, ICCSICi006-A, derived from a male Alzheimer's disease patient carrying the PSEN1-G206D mutation. Stem Cell Res. 2019 Oct;40:101574. Epub 2019 Sep 10 PubMed.
2. Raux G, Guyant-Maréchal L, Martin C, Bou J, Penet C, Brice A, Hannequin D, Frebourg T, Campion D. Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update. J Med Genet. 2005 Oct;42(10):793-5. Epub 2005 Jul 20 PubMed.
3. Wu YY, Cheng IH, Lee CC, Chiu MJ, Lee MJ, Chen TF, Hsu JL. Clinical phenotype of G206D mutation in the presenilin 1 gene in pathologically confirmed familial Alzheimer's disease. J Alzheimers Dis. 2011;25(1):145-50. PubMed.
4. Chen WT, Hsieh YF, Huang YJ, Lin CC, Lin YT, Liu YC, Lien CC, Cheng IH. G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca(2+) Accumulation. Mol Neurobiol. 2014 Nov 15; PubMed.
5. 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.
6. 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

No Available Further Reading