Mutations

PSEN1 V103G

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr14:73637725 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTC to GGC
Reference Isoform: PSEN1 isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was found in a screen of APP, PSEN1, and PSEN2 genes of 148 Chinese patients with familial AD who had at least two first-degree relatives with dementia (Gao et al., 2019).  The carrier of this mutation was a man who developed AD symptoms at age 42, and by age 44 was experiencing memory loss, executive dysfunction, disorientation, and dyscalculia. He was homozygous for APOE3. The mutation was absent from the gnomAD variant database.

Neuropathology
Unknown.

Biological Effect
The biological effect of this mutation is unknown, but analysis of a high-resolution cryo-EM structure of the human -secretase revealed this substitution likely decreases interaction with other hydrophobic residues (Gao et al., 2019Bai et al., 2015). In addition, in silico algorithms predicted the mutation to be probably damaging (PolyPhen), affecting protein function (SIFT), and disease-causing (MutationTaster), with a CADD score of 28.2. Also, orthologous sequence alignments revealed V103 is an evolutionarily conserved residue. The authors classified the mutation as “probably pathogenic,” following the algorithm by Guerreiro et al., 2010.

Last Updated: 25 Aug 2020

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References

Paper Citations

  1. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.
  2. . An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7. Epub 2015 Aug 17 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. . Mutation profile of APP, PSEN1, and PSEN2 in Chinese familial Alzheimer's disease. Neurobiol Aging. 2019 May;77:154-157. Epub 2019 Jan 31 PubMed.

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