Mutations

PSEN1 F105C

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637731 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TTT to TGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation was detected in a family from mainland China with three affected individuals over two generations. Disease in this family was described as a relatively pure amnestic syndrome without atypical motor or behavioral features. The proband developed progressive memory deficits at age 45, with later behavioral changes. Her brother developed similar symptoms beginning at age 51. Their father died with unclassified severe dementia at age 60, with onset around age 50. The mutation appears to segregate with disease in this family; it was present in the proband and her affected brother, but absent in an unaffected family member (Jiao et al., 2014; Deng et al., 2014).

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Neuropathology

Unknown. Neuroimaging of the two affected siblings showed enlarged ventricles, as well as atrophy in the hippocampus and frontotemporal regions (Deng et al., 2014).

Biological Effect

The biological effects of this mutation are unknown, but F105 has been identified as key for PSEN1's γ-processivity, the carboxypeptidase activity that trims Aβ intermediates to form shorter, secreted species (Liu et al., 2021). Moreover, this residue is conserved between PSEN1 and PSEN2, and several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted the substitution is damaging (Xiao et al., 2021). It has been classified as definitely pathogenic according to the algorithm proposed by Guerreiro et al., 2010 (Jiao et al., 2014; Deng et al., 2014) and as likely pathogenic (Xiao et al., 2021) using the ACMG-AMP guidelines

Last Updated: 26 Jul 2021

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . Mutational analysis in early-onset familial Alzheimer's disease in Mainland China. Neurobiol Aging. 2014 Aug;35(8):1957.e1-6. Epub 2014 Feb 20 PubMed.
  2. . Identification of a novel mutation in the presenilin 1 gene in a Chinese Alzheimer's disease family. Neurotox Res. 2014 Oct;26(3):211-5. Epub 2014 Apr 16 PubMed.
  3. . Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. J Biol Chem. 2021 Jan-Jun;296:100393. Epub 2021 Feb 8 PubMed.
  4. . APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
  5. . 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.
  6. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

External Citations

  1. gnomAD v2.1.1

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Mutational analysis in early-onset familial Alzheimer's disease in Mainland China. Neurobiol Aging. 2014 Aug;35(8):1957.e1-6. Epub 2014 Feb 20 PubMed.
  2. . Identification of a novel mutation in the presenilin 1 gene in a Chinese Alzheimer's disease family. Neurotox Res. 2014 Oct;26(3):211-5. Epub 2014 Apr 16 PubMed.

Other mutations at this position

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.