Mutations

PSEN1 Y115D

Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640278 T>G
dbSNP ID: rs63749962
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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 The proband’s father died at age 44 (unpublished findings; personal communication T.D. Bird, 2014).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., 2019, Liu et al., 2021). Cryo-electron microscopy studies suggest Y115 stabilizes the γ-secretase-Aβ complex via hydrogen bonding and van der Waals interactions (Odorčić et al., 2024; Guo et al., 2024; Jun 2024 news).

Analysis of secreted Aβs in the conditioned media of human embryonic kidney cells lacking endogenous PSENs and expressing Y115D along with wildtype APP, revealed increased Aβ42/40 ratio and decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios (Liu et al., 2021). 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. A subsequent study showed the Aβ37/42 ratio outperformed the standard Aβ42/Aβ40 ratio for distinguishing between control and AD samples (Liu et al., 2022, Apr 2022 news). This study also revealed Y115D increased levels of Aβ43.

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).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Y115D: Variant resides in a region that is both a mutational hot spot and of likely functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

Pathogenic (PS, PM, PP) Benign (BA, BS, BP)
Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)

Last Updated: 11 Jun 2024

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References

News Citations

  1. Caught in the Act: Cryo-EM Exposes γ-Secretase Catalytic Pose
  2. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. Szaruga M, Munteanu B, Lismont S, Veugelen S, Horré K, Mercken M, Saido TC, Ryan NS, De Vos T, Savvides SN, Gallardo R, Schymkowitz J, Rousseau F, Fox NC, Hopf C, De Strooper B, Chávez-Gutiérrez L. Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed. Correction.
  2. Arber C, Toombs J, Lovejoy C, Ryan NS, Paterson RW, Willumsen N, Gkanatsiou E, Portelius E, Blennow K, Heslegrave A, Schott JM, Hardy J, Lashley T, Fox NC, Zetterberg H, Wray S. Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry. 2020 Nov;25(11):2919-2931. Epub 2019 Apr 12 PubMed.
  3. Liu L, Lauro BM, Wolfe MS, Selkoe DJ. 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;296:100393. Epub 2021 Feb 8 PubMed.
  4. Odorčić I, Hamed MB, Lismont S, Chávez-Gutiérrez L, Efremov RG. Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform. Nat Commun. 2024 May 27;15(1):4479. PubMed.
  5. Guo X, Li H, Yan C, Lei J, Zhou R, Shi Y. Molecular mechanism of substrate recognition and cleavage by human γ-secretase. Science. 2024 Jun 7;384(6700):1091-1095. Epub 2024 Jun 6 PubMed.
  6. Liu L, Lauro BM, He A, Lee H, Bhattarai S, Wolfe MS, Bennett DA, Karch CM, Young-Pearse T, Dominantly Inherited Alzheimer Network (DIAN), Selkoe DJ. Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease. Alzheimers Dement. 2022 Mar 12; PubMed.
  7. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. 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

View Table

Alzpedia

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