Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173571 A>G
Position: (GRCh37/hg19):Chr14:73640279 A>G
dbSNP ID: rs63750450
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TAT to TGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation has been identified in multiple families and individuals worldwide suffering from familial early onset Alzheimer's disease (AD). Age of onset ranges from 33 to 54 years of age. 

It was first described in a Dutch family known as Family 1066, whose published pedigree included 10 affected family members over four generations. The clinical diagnosis of Alzheimer’s disease was pathologically confirmed in at least three members of the family. The mean age at onset was 42 years (range: 39 to 49 years). Disease in this family previously had been linked to chromosome 14 (van Duijn et al., 1994). The mutation segregated with disease in this family and was transmitted in an autosomal-dominant manner (Cruts et al., 1998).

The mutation was subsequently reported in several publications. One individual was identified during a genetic screen of patients with AD; no further clinical details were reported (Rogaeva et al., 2001). In another case, a family, known as Family 372, was reported with five affected family members over three generations. The mean age of onset in this family was 48 years (range: 36 to 54 years). No postmortem confirmation of the diagnosis was available at the time of the report (Janssen et al., 2003). The mutation was also detected in an individual with early onset AD, which was confirmed by autopsy. The proband experienced symptom onset at age 43 and died at age 52. The proband’s mother also had early onset dementia (onset at age 33; death at age 42) (unpublished findings, personal communication, T.D. Bird; 2014). In another study, consistent with previously reported families, the proband experienced symptom onset in her 40s. She died in her 50s with pathologically confirmed AD. She had a family history of dementia; her mother had experienced a similar disease course. The mutation was also detected in the proband’s daughter, who was asymptomatic at the time (Doran et al., 2006, meeting abstract).

The Y115C mutation was also found in a large French study reporting on 56 families affected by putatively familial early onset AD (Wallon et al., 2012). The mutation was detected in one proband (family EXT 238). DNA from two affected family members was not available, so segregation with disease could not be determined. Age of onset in this family was reported as 39 to 40 years of age, with a duration of three years.

Additional Y115C carriers with familial early onset AD have been reported in the U.K. (Ryan et al., 2016), France (Lanoiselee et al., 2017; Nicolas et al., 2024), Korea (Park et al., 2020), and China (Sun et al., 2021). Of note, Ryan and colleagues reported one of two carriers presenting with myoclonus, seizures, and/or cerebellar signs, and Sun and co-workers described a carrier with a slow gait (Sun et al., 2021). Additional symptoms in the latter included visuospatial disorientation, behavioral alterations, psychological abnormalities, and dysphasia.

The variant was absent from the gnomAD variant database (gnomAD v4.1.0, Jun 2024).

Neuropathology

Postmortem examination revealed pathology consistent with AD in Family 1066 (van Duijn et al., 1994). In one case, diffuse plaques were the predominant type of Aβ deposit, with a few primitive plaques observed in upper cortical layers (Maarouf et al., 2008).

In addition, the Korean individual was amyloid-positive as assessed by FMM-PET imaging, and MRI revealed atrophy in the bilateral medial temporal areas, while FDG-PET showed hypometabolism in bilateral temporoparietal areas (Park et al., 2020). Moreover, in one French individual, cerebrospinal fluid biomarkers, including Aβ42, tau, and phospho-tau, were consistent with AD (Lanoiselee et al., 2017).

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, Liu et al., 2021). Cryo-electron microscopy studies suggest 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 news).

Consistent with these findings, studies in cells and in isolated proteins in vitro have shown Y115C increases the Aβ42/40 ratio (De Jonghe et al., 1999, Sun et al., 2017, Liu et al., 2021). They have also revealed decreased Aβ37/40, Aβ37/42, and Aβ38/42 ratios, and reduced total secreted Aβ levels (Liu et al., 2021). Interestingly, the authors of this more recent study 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. Processing of the Notch substrate appeared to be unaffected (Maarouf et al., 2008).

In addition, as assessed in cortical neurons derived from patient induced pluripotent stem cells, Y115C may disrupt lysosome function and autophagy, leading to impaired lysosomal proteolysis and defective autophagosome clearance. These effects appear to be caused by accumulation of β-C-terminal fragments of APP (Hung and Livesey, 2018).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, M-CAP, and Reve in the VarCards database) predicted this variant is damaging (Park et al., 2020, Xiao et al., 2021, Sun et al., 2021). Based on the pathogenicity criteria developed by Guerreiro and colleagues (Guerreiro et al., 2010), this mutation was classified as definitely pathogenic (Lanoiselée et al., 2017).

Research Models

Induced pluripotent stem cell lines have been created from patient fibroblasts (Moore et al., 2015).

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.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

1. Caught in the Act: Cryo-EM Exposes γ-Secretase Catalytic Pose 7 Jun 2024

Paper Citations

1. van Duijn CM, Hendriks L, Farrer LA, Backhovens H, Cruts M, Wehnert A, Hofman A, Van Broeckhoven C. A population-based study of familial Alzheimer disease: linkage to chromosomes 14, 19, and 21. Am J Hum Genet. 1994 Oct;55(4):714-27. PubMed.
2. Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998 Jan;7(1):43-51. PubMed.
3. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
4. Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
5. Abstracts of the Sixteenth Meeting of the European Neurological Society. May 27-31, 2006. Lausanne, Switzerland. J Neurol. 2006 May;253 Suppl 2:II3-159. PubMed.
6. Wallon D, Rousseau S, Rovelet-Lecrux A, Quillard-Muraine M, Guyant-Maréchal L, Martinaud O, Pariente J, Puel M, Rollin-Sillaire A, Pasquier F, Le Ber I, Sarazin M, Croisile B, Boutoleau-Bretonnière C, Thomas-Antérion C, Paquet C, Moreaud O, Gabelle A, Sellal F, Sauvée M, Laquerrière A, Duyckaerts C, Delisle MB, Streichenberger N, Lannes B, Frebourg T, Hannequin D, Campion D. The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2012 Jan 1;30(4):847-56. PubMed.
7. 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.
8. Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
9. Nicolas G, Zaréa A, Lacour M, Quenez O, Rousseau S, Richard AC, Bonnevalle A, Schramm C, Olaso R, Sandron F, Boland A, Deleuze JF, Andriuta D, Anthony P, Auriacombe S, Balageas AC, Ballan G, Barbay M, Béjot Y, Belliard S, Benaiteau M, Bennys K, Bombois S, Boutoleau-Bretonnière C, Branger P, Carlier J, Cartz-Piver L, Cassagnaud P, Ceccaldi MP, Chauviré V, Chen Y, Cogez J, Cognat E, Contegal-Callier F, Corneille L, Couratier P, Cretin B, Crinquette C, Dauriat B, Dautricourt S, de la Sayette V, de Liège A, Deffond D, Demurger F, Deramecourt V, Derollez C, Dionet E, Doco Fenzy M, Dumurgier J, Dutray A, Etcharry-Bouyx F, Formaglio M, Gabelle A, Gainche-Salmon A, Godefroy O, Graber M, Gregoire C, Grimaldi S, Gueniat J, Gueriot C, Guillet-Pichon V, Haffen S, Hanta CR, Hardy C, Hautecloque G, Heitz C, Hourregue C, Jonveaux T, Jurici S, Koric L, Krolak-Salmon P, Lagarde J, Lanoiselée HM, Laurens B, Le Ber I, Le Guyader G, Leblanc A, Lebouvier T, Levy R, Lippi A, Mackowiak MA, Magnin E, Marelli C, Martinaud O, Maureille A, Migliaccio R, Milongo-Rigal E, Mohr S, Mollion H, Morin A, Nivelle J, Noiray C, Olivieri P, Paquet C, Pariente J, Pasquier F, Perron A, Philippi N, Planche V, Pouclet-Courtemanche H, Rafiq M, Rollin-Sillaire A, Roué-Jagot C, Saracino D, Sarazin M, Sauvée M, Sellal F, Teichmann M, Thauvin C, Thomas Q, Tisserand C, Turpinat C, Van Damme L, Vercruysse O, Villain N, Wagemann N, Charbonnier C, Wallon D. Assessment of Mendelian and risk-factor genes in Alzheimer disease: A prospective nationwide clinical utility study and recommendations for genetic screening. Genet Med. 2024 May;26(5):101082. Epub 2024 Jan 24 PubMed.
10. Park JE, Kim HJ, Kim YE, Jang H, Cho SH, Kim SJ, Na DL, Won HH, Ki CS, Seo SW. Analysis of dementia-related gene variants in APOE ε4 noncarrying Korean patients with early-onset Alzheimer's disease. Neurobiol Aging. 2020 Jan;85:155.e5-155.e8. Epub 2019 May 22 PubMed.
11. Sun L, Zhang J, Su N, Zhang S, Yan F, Lin X, Yu J, Li W, Li X, Xiao S. Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing. Front Aging Neurosci. 2021;13:745407. Epub 2021 Oct 14 PubMed.
12. Maarouf CL, Daugs ID, Spina S, Vidal R, Kokjohn TA, Patton RL, Kalback WM, Luehrs DC, Walker DG, Castaño EM, Beach TG, Ghetti B, Roher AE. Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. Mol Neurodegener. 2008 Nov 20;3:20. PubMed.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. De Jonghe C, Cruts M, Rogaeva EA, Tysoe C, Singleton A, Vanderstichele H, Meschino W, Dermaut B, Vanderhoeven I, Backhovens H, Vanmechelen E, Morris CM, Hardy J, Rubinsztein DC, St George-Hyslop PH, Van Broeckhoven C. Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Abeta42 secretion. Hum Mol Genet. 1999 Aug;8(8):1529-40. PubMed.
19. 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.
20. Hung CO, Livesey FJ. Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer's Disease. Cell Rep. 2018 Dec 26;25(13):3647-3660.e2. PubMed.
21. 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.
22. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
23. Moore S, Evans LD, Andersson T, Portelius E, Smith J, Dias TB, Saurat N, McGlade A, Kirwan P, Blennow K, Hardy J, Zetterberg H, Livesey FJ. APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 2015 May 5;11(5):689-96. Epub 2015 Apr 23 PubMed.

Further Reading