Mutations

PSEN1 L113Q

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637755 T>A
dbSNP ID: rs63751399
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CTA to CAA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This mutation, located in the first hydrophilic loop of the presenilin-1 protein, was detected in a Greek patient identified as p.62. She experienced symptom onset at age 33 and died three years later. Prominent symptoms included rapidly progressing dementia, drop attacks, myoclonic seizures, and bilateral spasticity. The patient had a family history of very early onset dementia. The patient’s brother and mother died at ages 35 and 36, respectively, and the family indicated that her maternal grandfather and uncle had had similar disease courses (Finckh et al., 2005).

The variant was absent from the gnomAD variant database (May 2021).

Neuropathology

Autopsy confirmed the diagnosis of Alzheimer’s disease, reporting neuritic plaques (Braak stage C), neurofibrillary tangles (stage VI), and severe amyloid angiopathy (Finckh et al., 2005).

Biological Effect

L113 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). Consistently, an in vitro assay using purified proteins to test the ability of this mutant to cleave the APP-C99 substrate revealed decreased Aβ40 production resulting in an approximately 5-fold increase in the Aβ42/Aβ40 ratio (Sun et al., 2017).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021)

Last Updated: 08 Sep 2021

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References

Paper Citations

  1. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  2. . 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.
  3. . Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 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.

External Citations

  1. gnomAD variant database

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.

Other mutations at this position

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