Mutations

PSEN1 G206S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS2, PS3, PS4, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73659419 G>A
dbSNP ID: rs63750569
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GGT to AGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

The G206S mutation has been reported in three families and two individuals with early onset dementia. It was first reported in a single Alzheimer’s disease (AD) patient in 2001, although clinical details were not included and segregation with disease could not be determined (Rogaeva et al., 2001).

This mutation was subsequently reported in a large kindred known as KRI 001 with 15 affected family members. All affected members fulfilled NINCDS-ADRDA criteria for probable or definite Alzheimer’s disease. Age of onset ranged from 30 to 35 in this family. Segregation of the mutation with disease was reportedly demonstrated, but further details were not published (Raux et al., 2005).

In addition, a Korean family with four affected family members has been reported. The proband, known as patient 2 in the report, experienced symptom onset at age 35 and met NINCDS-ADRDA criteria for probable Alzheimer’s disease. Family members experienced onset in their 40s (Park et al., 2008).

The mutation was also found, de novo, in a 40-year-old Chinese man with early onset AD (Liu et al., 2019). Memory decline was progressive, starting at age 37. Neither of his parents, both healthy and above age 60, carried the mutation.

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

Neuropathology

Postmortem analysis has not been reported. Neuroimaging in the Korean proband showed bilateral frontotemporal and parietal hypometabolism by PET and diffuse brain atrophy with enlarged ventricles by CT (Park et al., 2008). In the Chinese patient, three years after onset, MRI showed bilateral hippocampal atrophy, mild lateral ventricle enlargement, and cerebral white matter degeneration. Moreover, PiB-PET revealed diffuse amyloid accumulation in the cortex (Liu et al., 2019).

Biological Effect

An in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed it drastically reduces Aβ40 and Aβ42 production, and increases the Aβ42/Aβ40 ratio approximately 10-fold (Sun et al., 2017). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment suggests mutations in this residue 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).

Although some in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 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.

PS2-S

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

PS3-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. G206S: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. G206S: 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. G206S: 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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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: 22 Feb 2022

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References

News Citations

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

Paper Citations

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . 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. . Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer's disease. J Korean Med Sci. 2008 Apr;23(2):213-7. PubMed.
  4. . Diagnostic Approach of Early-Onset Dementia with Negative Family History: Implications from Two Cases of Early-Onset Alzheimer's Disease with De Novo PSEN1 Mutation. J Alzheimers Dis. 2019;68(2):551-558. PubMed.
  5. . 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.
  6. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  7. . 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
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
  2. . 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.

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