Mutations

PSEN1 Y115H

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
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).

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).

Neuropathology

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

Biological Effect

In various cell types, mutant PSEN1 increased the levels of secreted Aβ42 and the ratio of Aβ42/Aβ40 (Murayama et al., 1999Shioi et al., 2007). Additionally, the Y115H mutation decreased the intracellular levels of Aβ40 and increased the intracellular levels of Aβ42. Notch cleavage was also reduced (Sannerud et al., 2016). More recent experiments, analyzing the Aβ peptidome of neurons derived from patient iPSCs, indicate the Y115H mutant increases Aβ42/Aβ40, Aβ42/Aβ38, and Aβ43/Aβ40 ratios, while leaving Aβ38/Aβ40, an indicator of γ-secretase endopeptidase activity, unchanged (Arber et al., 2019; see April 2019 news). The elevated ratios suggest inefficient carboxypeptidase activity, predisposing neurons to accumulate longer Aβ fragments, possibly due to the mutation's location near the substrate docking domain. Moreover, mass spectrometric analysis of Aβ peptides in the cell media showed Y115H significantly increased BACE1-α-secretase products.

Consistent with the mutation causing longer Aβ fragment accumulation, in vitro experiments using isolated proteins indicated Y115H drastically reduces Aβ40 and Aβ38 levels, while not significantly affecting those 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).  

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). 

Last Updated: 17 Apr 2019

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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. . Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
  4. . 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.
  5. . 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.
  6. . 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.
  7. . Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry. 2019 Apr 12; PubMed.
  8. . The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
  9. . 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.
  10. . Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed.
  11. . 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.

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.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

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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