Mutations

PSEN1 L173S

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653598 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTG to TCG
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was found in a Han Chinese individual diagnosed with possible AD according to the NINCDS-ADRDA and DSM-IV criteria (Wang et al., 2019). The patient had at least one affected first- or second-degree relative and age at onset was 38 years. 

Neuropathology

Unknown

Biological Effect

The mutation was predicted to be damaging by four different algorithms, with a PHRED-CADD score of 24.1. A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates the L173 residue is apposed to the APP transmembrane helix, with its side-chain reaching towards the interior of the substrate-binding pore (Zhou et al., 2019; Jan 2019 news).

Last Updated: 13 Aug 2019

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References

News Citations

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

Paper Citations

  1. . Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease. J Psychiatr Res. 2019 Jun;113:141-147. Epub 2019 Mar 30 PubMed.
  2. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease. J Psychiatr Res. 2019 Jun;113:141-147. Epub 2019 Mar 30 PubMed.

Other mutations at this position

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