Mutations

PSEN1 Y115D

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640278 T>G
dbSNP ID: rs63749962
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TAT to GAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was detected in a single individual with early onset dementia. Symptoms occurred very early, at age 29 in the proband and age 31 in the proband’s affected father. The proband’s father died at age 44 (unpublished findings; personal communication T.D. Bird, 2014). 

The variant was absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Neuropathology

Postmortem examination showed neuropathology consistent with AD.

Biological Effect

Y115 has been identified as key for PSEN1's γ-processivity, the carboxypeptidase activity that trims Aβ intermediates to form shorter, secreted species, and this mutant appears to reduce it (Szaruga et al., 2017, Arber et al., 2019Liu et al., 2021). Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing this mutant along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios. This mutant also reduced total secreted Aβ levels. Interestingly, the authors also reported that Aβ42/40, Aβ38/42, and particularly Aβ37/42, ratios each correlated with reported ages of onset of clinical impairment across 16 PSEN1 mutations. Moreover, they proposed this residue as a key target for heterocyclic γ-secretase modulators (GSMs) to stimulate processing of pathogenic Aβ peptides.

Although one study using several silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, REVEL, and Reve in the VarCards database) yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

Last Updated: 20 Sep 2021

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References

Paper Citations

  1. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed.
  2. . Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry. 2019 Apr 12; 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.

External Citations

  1. gnomAD v2.1.1
  2. CADD v.1.6

Further Reading

No Available Further Reading

Protein Diagram

Other mutations at this position

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