Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease
De Roeck, Arne (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
Van den Bossche, Tobi (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
van der Zee, Julie (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
Verheijen, Jan (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
De Coster, Wouter (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
Van Dongen, Jasper (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
Dillen, Lubina (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
Baradaran-Heravi, Yalda (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
Heeman, Bavo (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
Sanchez-Valle, Raquel (Hospital Clínic i Provincial de Barcelona)
Llado Plarrumani, Albert (Hospital Clínic i Provincial de Barcelona)
Nacmias, Benedetta (University of Florence)
Sorbi, Sandro (University of Florence)
Gelpi, Ellen (Hospital Clínic i Provincial de Barcelona)
Grau-Rivera, Oriol (Hospital Clínic i Provincial de Barcelona)
Gómez-Tortosa, Estrella (Hospital Universitario Fundación Jiménez Díaz)
Pastor, Pau (Hospital Universitari MútuaTerrassa (Terrassa, Catalunya))
Ortega-Cubero, Sara (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Pastor, Maria A. (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Graff, Caroline (Karolinska Institutet (Estocolm, Suècia). Center for Alzheimer Research)
Thonberg, Håkan (Karolinska Institutet (Estocolm, Suècia). Center for Alzheimer Research)
Benussi, Luisa (Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy)
Ghidoni, Roberta (Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy)
Binetti, Giuliano (Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy)
de Mendonça, Alexandre (University of Lisbon, Portugal)
Martins, Madalena (University of Lisbon, Portugal)
Borroni, Barbara (Centre for Neurodegenerative Disorders, University of Brescia, Italy.)
Padovani, Alessandro (Centre for Neurodegenerative Disorders, University of Brescia, Brescia, Italy)
Almeida, Maria Rosário (Center for Neuroscience and Cell Biology, University of Coimbra, Portugal)
Santana, Isabel (University of Coimbra)
Diehl-Schmid, Janine (Technische Universität München)
Alexopoulos, Panagiotis (Technische Universität München)
Clarimón, Jordi (Institut d'Investigació Biomèdica Sant Pau)
Lleó, Alberto (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Fortea, Juan (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Tsolaki, Magda (Aristotle University of Thessaloniki)
Koutroumani, Maria (Aristotle University of Thessaloniki)
Matej, Radoslav (Charles University, Prague, Czech Republic)
Rohan, Zdenek (Charles University, Prague, Czech Republic)
De Deyn, Peter Paul (Institute Born-Bunge, University of Antwerp, Belgium)
Engelborghs, Sebastiaan (Institute Born-Bunge, University of Antwerp, Belgium)
Cras, Patrick (Institute Born-Bunge, University of Antwerp, Belgium)
Van Broeckhoven, Christine (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
Sleegers, Kristel (VIB Center for Molecular Neurology, VIB, Antwerp, Belgium)
Universitat Autònoma de Barcelona

Fecha:	2017
Resumen:	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.
Ayudas:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2014SGR-0235 Instituto de Salud Carlos III PI12-01311 Instituto de Salud Carlos III PI14-00282
Nota:	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).
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Early Onset Alzheimer's disease ; ATP-Binding Cassette ; Sub-Family A ; Member 7 (ABCA7) ; Third-generation long-read sequencing ; RNA sequencing ; Loss-of-function ; Modifier
Publicado en:	Acta Neuropathologica, Vol. 134 (april 2017) , p. 475-487, ISSN 1432-0533

DOI: 10.1007/s00401-017-1714-x
PMID: 28447221

13 p, 1.2 MB

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