Mutations

PSEN1 Y115H

Overview

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

Findings

This mutation was first identified in a small French kindred known as Family ALZ 025 or ALZ 25. This family had two affected individuals over two generations, the proband and the proband’s father, with onset at age 35 and 37. The mutation was absent in the proband’s unaffected mother, who was cognitively healthy at age 80, and absent in 50 unrelated control subjects. The proband’s paternal grandparents were unaffected by age 75, so the authors speculated the mutation may have arisen de novo in the proband’s father (Campion et al., 1995; Campion et al., 1999). A second family, also from France, has been identified. That family, known as ALZ 76, had three affected members over three generations, with age at onset ranging from 36 to 47 years (Campion et al., 1999). In a subsequent study, seizures were reported in two French mutation carriers (Zarea et al. 2016). The average time between AD onset and first seizure was three years.

The mutation was also found in a German kindred with at least four affected individuals over two generations. The proband was a 44-year-old patient ("Patient p.39") who died severely demented after three years. The proband’s sister also died around age 40 with symptoms including epileptic seizures and myoclonus. The proband’s brother died at age 43 after a very similar disease course; autopsy confirmed AD. The proband’s mother died severely demented in her early 40s (Finckh et al., 2005).

More recently, the mutation was identified in a retrospective analysis of genotypic and phenotypic data from individuals with autosomal-dominant familial AD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, U.K (Ryan et al., 2016). A family with four affected individuals and a mean age at onset of 34 years was reported. One of the four patients presented with seizures, and one of two patients examined had myoclonus or spastic paraparesis. Interestingly, one patient had early extrapyramidal signs with markedly asymmetric features consistent with corticobasal syndrome.

This variant is absent from the gnomAD variant database (May 2021).

Neuropathology

Postmortem analysis revealed pathology consistent with AD (Finckh et al., 2005).

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 (Szaruga et al., 2017, Arber et al., 2019April 2019 newsLiu et al., 2021). Consistently, several studies in cells have shown this mutant increases the Aβ42/40 ratio (Murayama et al., 1999Shioi et al., 2007, Arber et al., 2019, Liu et al., 2021). They have also revealed increased Aβ42/Aβ38, and Aβ43/Aβ40 ratios with an unchanged Aβ38/Aβ40, an indicator of γ-secretase endopeptidase activity (Arber et al., 2019), as well as decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios (Liu et al., 2021). Arber and colleagues suggested the apparent inefficiency in carboxypeptidase activity could be due to the mutation's location near the substrate docking domain. Moreover, they reported that mass spectrometric analysis of Aβ peptides in the cell media showed Y115H significantly increased BACE1-α-secretase products. Liu and co-workers found Y115H-expressing cells secreted more total Aβ peptides than those expressing wildtype PSEN1, seemingly increasing Aβ42 production at the expense of Aβ37 and Aβ 38, while maintaining Aβ40 production at wildtype levels.

Although not exactly mirroring the cellular results, in vitro experiments using isolated proteins are consistent with the mutation causing longer Aβ fragment accumulation. These studies indicated Y115H drastically reduces Aβ40 and Aβ38 levels, while not significantly affecting those of Aβ43 and Aβ42 of Aβ43 and Aβ42 (Chavez-Gutierrez et al, 2012, Sun et al., 2017). Moreover, in vitro experiments testing the mutant's γ-secretase activity at different temperatures showed it increases enzyme-Aβn complex dissociation rates, enhancing the release of longer Aβ peptides (Szaruga et al., 2017).  

In contrast to Sun and colleagues who did not find a correlation between Aβ42/40 and AD age of onset working with isolated proteins (Sun et al., 2017), Liu and colleagues, working with cells, 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 (Liu et al., 2021).  Moreover, they proposed Y115 as a key target for heterocyclic γ-secretase modulators (GSMs) to stimulate processing of pathogenic Aβ peptides.

A dominant-negative effect on wild-type PSEN1 may also contribute to Y115H pathogenecity as suggested by observations indicating the mutant suppresses Aβ production by wild-type PSEN1 in vitro. The effect was specifically sensitive to a detergent that disrupts PSEN1 oligomerization, indicating the mutant may disrupt wild-type activity via hetero-oligomerization (Zhou et al., 2017).

Interestingly, notch cleavage was also reported as reduced (Sannerud et al., 2016). Consistently, premature neurogenesis was observed during the differentiation of induced pluripotent stem cells harboring the mutation in a 2D model of cortical differentiation, as well as in the generation of a 3D cerebral organoid (Arber et al., 2021).

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: 30 Jul 2021

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References

News Citations

  1. Familial Alzheimer’s Mutations: Different Mechanisms, Same End Result

Paper Citations

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
  2. . Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
  3. . Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
  4. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  5. . Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
  6. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed.
  7. . Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry. 2019 Apr 12; PubMed.
  8. . 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.
  9. . Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999 Apr 9;265(1):61-3. PubMed.
  10. . FAD mutants unable to increase neurotoxic Abeta 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. J Neurochem. 2007 May;101(3):674-81. Epub 2007 Jan 24 PubMed.
  11. . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
  12. . 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.
  13. . Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization. Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12731-12736. Epub 2017 Oct 9 PubMed.
  14. . Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool. Cell. 2016 Jun 30;166(1):193-208. Epub 2016 Jun 9 PubMed.
  15. . Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis. Cell Rep. 2021 Jan 12;34(2):108615. PubMed.
  16. . 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

Papers

  1. . Additive effects of PS1 and APP mutations on secretion of the 42-residue amyloid beta-protein. Neurobiol Dis. 1998 Aug;5(2):107-16. PubMed.

Protein Diagram

Primary Papers

  1. . Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.

Other mutations at this position

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