Mutations

PSEN1 W165C (G>T)

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73653575 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TGG to TGT
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was first identified in a whole-exome sequencing search for genetic variants associated with AD in 17 individuals from India with advanced AD. All patients had one or more first-degree relatives diagnosed with dementia. The search was focused on coding regions previously implicated in dementia (Syama et al., 2018). Affected patients developed disease in their 40s, with rapid progression.

The mutation was subsequently found in a Korean man with a family history of early onset AD (Van Giau et al., 2019). At age 50, the proband presented with memory loss, as well as temporal and spatial disorientation. His deceased mother had suffered from AD with onset in her 50s, and his deceased brother experienced AD onset in his 40s. The proband had an APOE2/3 genotype.

The mutation was absent from the Korean Reference Genome Database, as well as from the gnomAD, ExAC, and 1000 genomes databases.

Neuropathology
Although no autopsy observations were reported for this mutation, in one patient, MRI showed diffuse cerebral and cerebellar atrophy (Syama et al., 2018) and in another mild, bilateral atrophy of the hippocampus and bilateral lobe, three years after symptom onset (Van Giau et al., 2019). Moreover, in the latter patient, FBB-PET at five years after symptom onset showed increased amyloid deposition in the parietal, frontal, and temporal lobes, as well as in the precuneus.

Biological Effect
The biological effect of this mutation is unknown, but SIFT, PolyPhen-2, and PROVEAN algorithms predicted it is deleterious (Syama et al., 2018; Van Giau et al., 2019). In addition, three-dimensional modeling programs suggested the mutation induces significant conformational changes, disrupting several hydrogen bonds with other amino acids and creating new interactions (Van Giau et al., 2019). A cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that, in wild-type PSEN1, W165 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: 09 Aug 2019

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References

News Citations

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

Paper Citations

  1. . A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer's disease. BMC Neurol. 2019 Aug 7;19(1):188. PubMed.
  2. . Mutation burden profile in familial Alzheimer's disease cases from India. Neurobiol Aging. 2018 Apr;64:158.e7-158.e13. Epub 2017 Dec 12 PubMed.
  3. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Other Citations

  1. Syama et al., 2018

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutation burden profile in familial Alzheimer's disease cases from India. Neurobiol Aging. 2018 Apr;64:158.e7-158.e13. Epub 2017 Dec 12 PubMed.

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