Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease
| Autor: | Peter Paul De Deyn, Kristel Sleegers, Raquel Sánchez-Valle, Ellen Gelpi, Zdenek Rohan, Isabel Santana, Julie van der Zee, Patrick Cras, Panagiotis Alexopoulos, Madalena Martins, A. Lleo, Håkan Thonberg, Alessandro Padovani, Giuliano Binetti, Sandro Sorbi, Albert Lladó, Sebastiaan Engelborghs, Bavo Heeman, Tobi Van den Bossche, Alexandre de Mendonça, Pau Pastor, Christine Van Broeckhoven, Arne De Roeck, Maria Koutroumani, Janine Diehl-Schmid, Maria Rosário Almeida, Juan Fortea, Jasper Van Dongen, Sara Ortega-Cubero, Roberta Ghidoni, Lubina Dillen, Oriol Grau-Rivera, Estrella Gómez-Tortosa, Luisa Benussi, Maria A. Pastor, Benedetta Nacmias, Wouter De Coster, Caroline Graff, Jordi Clarimón, Magda Tsolaki, Jan Verheijen, Yalda Baradaran-Heravi, Barbara Borroni, Radoslav Matěj |
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| Přispěvatelé: | European Early-Onset Dementia, Clinical sciences, Neurology, Physiotherapy, Human Physiology and Anatomy, Pathologic Biochemistry and Physiology, European Early-Onset Dementia (EU EOD) consortium |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Male endocrine system diseases ATP-Binding Cassette Transporters/genetics Early Onset Alzheimer’s disease Member 7 (ABCA7) Biology medicine.disease_cause Polymorphism Single Nucleotide Pathology and Forensic Medicine ABCA7 Loss-of-function 03 medical and health sciences Cellular and Molecular Neuroscience Third-generation long-read sequencing Alzheimer Disease medicine Coding region Humans Early-onset Alzheimer's disease Genetic Predisposition to Disease Age of Onset Modifier Gene Genetic Association Studies Aged Medicine(all) Genetics Alzheimer Disease/genetics Mutation Original Paper Sub-Family A Alternative splicing RNA sequencing Middle Aged medicine.disease Penetrance 3. Good health 030104 developmental biology biology.protein Early Onset Alzheimer's disease ATP-Binding Cassette Transporters Female ATP-Binding Cassette Neurology (clinical) Human medicine Age of onset |
| Zdroj: | Acta neuropathologica Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona Acta Neuropathologica |
| ISSN: | 0001-6322 |
| Popis: | Altres ajuts: The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The research was funded in part by the European Commission Seventh Framework Programme for research, technological development, and demonstration under grant agreement 305299 (AgedBrainSYSBIO), the Belgian Science Policy Office Interuniversity Attraction Poles program, the Alzheimer Research Foundation (SAO-FRA), the Flemish government-initiated Flanders Impulse Program on Networks for Dementia Research (VIND), the Flemish government-initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO), the VIB Technology Fund, the University of Antwerp Research Fund, Belgium; European Regional Development Fund, the Italian Ministry of Health (Ricerca Corrente and RF-2010-2319722), and the Fondazione Cassa di Risparmio di Pistoia e Pescia grant (2014.0365). Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD. |
| Databáze: | OpenAIRE |
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