Mutations

PSEN1 G206S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
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 two 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 in a Chinese individual with early onset AD and no family history of disease (Liu et al., 2019). The mutation appears to have arisen de novo in this case.

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).

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).

Last Updated: 14 Aug 2019

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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.

Further Reading

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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.

Other mutations at this position

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