Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173570 T>C
Position: (GRCh37/hg19):Chr14:73640278 T>C
dbSNP ID: rs63749962
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: 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., 2019, April 2019 news, Liu et al., 2021). Two in-depth studies of the Aβ peptides produced by cells transfected with this variant revealed a deleterious effect, decreasing both the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Petit et al., 2022; Liu et al., 2022; Apr 2022 news). Both ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset.

Moreover, a subsequent study reported the Aβ (37 + 38 + 40) / (42 + 43) ratio associated with transfected mutant cells as 29.78 percent that of control cells expressing wildtype PSEN1 (Schultz et al., 2024; Aug 2024 conference news). This reduction was strongly associated, not only with age at onset, but with biomarker and cognitive trajectories.

Consistent with these findings, several studies in cells have shown this mutant increases the Aβ42/40 ratio (Murayama et al., 1999; Shioi 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.

Cryo-electron microscopy studies have provided key insights into Y115’s role during the sequential cleavage of Aβ, suggesting it stabilizes the γ-secretase-Aβ complex via hydrogen bonding and van der Waals interactions (Odorčić et al., 2024; Guo et al., 2024; Jun 2024).

A dominant-negative effect on wild-type PSEN1 may also contribute to Y115H pathogenicity 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)

Pathogenicity

Alzheimer's Disease : Pathogenic

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. Y115H: 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.

PP1-M

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. Y115H: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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: 27 Aug 2024

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References

News Citations

Paper Citations

Campion D, Flaman JM, Brice A, Hannequin D, Dubois B, Martin C, Moreau V, Charbonnier F, Didierjean O, Tardieu S. Mutations of the presenilin I gene in families with early-onset Alzheimer's disease. Hum Mol Genet. 1995 Dec;4(12):2373-7. PubMed.
Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999 Sep;65(3):664-70. PubMed.
Zarea A, Charbonnier C, Rovelet-Lecrux A, Nicolas G, Rousseau S, Borden A, Pariente J, Le Ber I, Pasquier F, Formaglio M, Martinaud O, Rollin-Sillaire A, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Ceccaldi M, Gabelle A, Chamard L, Blanc F, Sellal F, Paquet C, Campion D, Hannequin D, Wallon D, PHRC GMAJ Collaborators. Seizures in dominantly inherited Alzheimer disease. Neurology. 2016 Aug 30;87(9):912-9. Epub 2016 Jul 27 PubMed.
Finckh U, Kuschel C, Anagnostouli M, Patsouris E, Pantes GV, Gatzonis S, Kapaki E, Davaki P, Lamszus K, Stavrou D, Gal A. Novel mutations and repeated findings of mutations in familial Alzheimer disease. Neurogenetics. 2005 May;6(2):85-9. Epub 2005 Mar 18 PubMed.
Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. 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.
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.
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.
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.
Petit D, Fernández SG, Zoltowska KM, Enzlein T, Ryan NS, O'Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chávez-Gutiérrez L. Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
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.
Schultz SA, Liu L, Schultz AP, Fitzpatrick CD, Levin R, Bellier JP, Shirzadi Z, Joseph-Mathurin N, Chen CD, Benzinger TL, Day GS, Farlow MR, Gordon BA, Hassenstab JJ, Jack CR Jr, Jucker M, Karch CM, Lee JH, Levin J, Perrin RJ, Schofield PR, Xiong C, Johnson KA, McDade E, Bateman RJ, Sperling RA, Selkoe DJ, Chhatwal JP, Dominantly Inherited Alzheimer Network. γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). Lancet Neurol. 2024 Sep;23(9):913-924. Epub 2024 Jul 26 PubMed.
Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. 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.
Shioi J, Georgakopoulos A, Mehta P, Kouchi Z, Litterst CM, Baki L, Robakis NK. 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.
Chávez-Gutiérrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, Lismont S, Zhou L, Van Cleynenbreugel S, Esselmann H, Wiltfang J, Serneels L, Karran E, Gijsen H, Schymkowitz J, Rousseau F, Broersen K, De Strooper B. The mechanism of γ-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012 May 16;31(10):2261-74. Epub 2012 Apr 13 PubMed.
Sun L, Zhou R, Yang G, Shi Y. 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.
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.
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.
Zhou R, Yang G, Shi Y. 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.
Sannerud R, Esselens C, Ejsmont P, Mattera R, Rochin L, Tharkeshwar AK, De Baets G, De Wever V, Habets R, Baert V, Vermeire W, Michiels C, Groot AJ, Wouters R, Dillen K, Vints K, Baatsen P, Munck S, Derua R, Waelkens E, Basi GS, Mercken M, Vooijs M, Bollen M, Schymkowitz J, Rousseau F, Bonifacino JS, Van Niel G, De Strooper B, Annaert W. 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.
Arber C, Lovejoy C, Harris L, Willumsen N, Alatza A, Casey JM, Lines G, Kerins C, Mueller AK, Zetterberg H, Hardy J, Ryan NS, Fox NC, Lashley T, Wray S. Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis. Cell Rep. 2021 Jan 12;34(2):108615. PubMed.
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.

Mutations

PSEN1 Y115H

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