PSEN1 W165C (G>T)


Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73653575 G>T
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TGG to TGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6


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 is also referred to as W161C in this study as it maps to amino acid 161 in the 463-amino acid PSEN1 isoform).

The mutation was subsequently found in a Korean man and a Chinese Han woman. The Korean man had a family history of early onset AD (Van Giau et al., 2019). At age 50, he 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. He had an APOE2/3 genotype. The Chinese woman developed progressive memory loss starting at age 48 (Han et al. 2020). By age 53, she had emotional instability, difficulties with language, and slowed movements. Her father, who died at age 55, experienced similar symptoms.

The mutation was absent from the Korean Reference Genome Database, as well as from the gnomAD, ExAC, and 1000 genomes databases (Van Giau et al., 2019).

Although no autopsy observations were reported for this mutation, MRI showed diffuse cerebral and cerebellar atrophy in one patient (Syama et al., 2018), global brain atrophy without vascular lesions in another (Han et al., 2020), and mild, bilateral atrophy of the hippocampus and bilateral lobe, three years after symptom onset, in a third patient (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; Han et al., 2020). 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: 22 Oct 2020


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News Citations

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

Paper Citations

  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.
  2. . A pathogenic PSEN1 Trp165Cys mutation associated with early-onset Alzheimer's disease. BMC Neurol. 2019 Aug 7;19(1):188. PubMed.
  3. . Genetic Analysis of Chinese Patients with Early-Onset Dementia Using Next-Generation Sequencing. Clin Interv Aging. 2020;15:1831-1839. Epub 2020 Oct 2 PubMed.
  4. . Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Further Reading


  1. . APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease. Int J Mol Sci. 2019 Sep 25;20(19) PubMed.

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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