Mutations

PSEN1 F205_G206del;insC

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73659417 TTG>---
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Deletion
Codon Change: TTTGGT to T---GT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 7

Findings

This mutation is a deletion of the last two nucleotides of PSEN1 codon 205 and the first nucleotide of codon 206, resulting in loss of the corresponding phenylalanine and glycine, and insertion of a cysteine. It was identified in a French study that screened 129 individuals with sporadic AD diagnosed according to the National Institute of Aging–Alzheimer’s Association criteria with an age at onset below 51 (Lanoiselée et al., 2017). The mutation carrier had progressive cognitive decline beginning at age 42, a disease duration of five years, and carried the APOE2 and APOE3 alleles. Examination of parental DNA indicated the mutation arose de novo. The mutation was absent from the exome database ExAC, including approximately 60,000 controls.

Neuropathology
No neuropathological data were available, but levels of Aβ42, tau, and phospho-tau in the mutation carrier’s cerebrospinal fluid were in the AD pathological range (376 pg/ml; 397 pg/ml; and 91 pg/ml, respectively).

Biological Effect
The biological effect of this mutation is unknown, but several mutations in G206 have been associated with AD and altered Aβ production. Moreover, 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). Based on the pathogenicity criteria developed by Guerreiro and colleagues (Guerreiro et al., 2010), this mutation was classified as probably pathogenic (Lanoiselée et al., 2017).

Last Updated: 14 Aug 2019

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References

Mutation Position Table Citations

  1. PSEN1 G206 Mutations

News Citations

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

Paper Citations

  1. . 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.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
  3. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . 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.

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