Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease
Por:
De Roeck A., Van den Bossche T., van der Zee J., Verheijen J., De Coster W., Van Dongen J., Dillen L., Baradaran-Heravi Y., Heeman B., Sanchez-Valle R., Lladó A., Nacmias B., Sorbi S., Gelpi E., Grau-Rivera O., Gómez-Tortosa E., Pastor P., Ortega-Cubero S., Pastor M.A., Graff C., Thonberg H., Benussi L., Ghidoni R., Binetti G., de Mendonça A., Martins M., Borroni B., Padovani A., Almeida M.R., Santana I., Diehl-Schmid J., Alexopoulos P., Clarimon J., Lleó A., Fortea J., Tsolaki M., Koutroumani M., Matej R., De Deyn P., Engelborghs S., Cras P., Van Broeckhoven C., Sleegers K., Bessi V., Bagnoli S., do Couto F.S., Verdelho A., Fratiglioni L., Rohan Z., Razquin C., Lorenzo E., Iglesias E., Seijo-Martínez M., Rene R., Gascon J., Campdelacreu J., Blesa R.
Publicada:
1 ene 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. © 2017, The Author(s).
Filiaciones:
De Roeck A.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Van den Bossche T.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Department of Neurology, Antwerp University Hospital, Edegem, Belgium
Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium
van der Zee J.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Verheijen J.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
De Coster W.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Van Dongen J.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Dillen L.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Baradaran-Heravi Y.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Heeman B.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Sanchez-Valle R.:
Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Lladó A.:
Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Nacmias B.:
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
Sorbi S.:
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
IRCCS Don Gnocchi, Florence, Italy
Gelpi E.:
Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Grau-Rivera O.:
Neurological Tissue Bank of the Biobanc, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Gómez-Tortosa E.:
Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain
Pastor P.:
Memory Unit, Department of Neurology, University Hospital Mútua de Terrassa, University of Barcelona School of Medicine, Terrassa, Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Ortega-Cubero S.:
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Pastor M.A.:
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
Graff C.:
Department of Neurobiology, Care Sciences and Society (NVS), Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Stockholm, Sweden
Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden
Thonberg H.:
Department of Neurobiology, Care Sciences and Society (NVS), Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Stockholm, Sweden
Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden
Benussi L.:
Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy
Ghidoni R.:
Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy
Binetti G.:
Molecular Markers Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy
MAC Memory Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy
de Mendonça A.:
Faculty of Medicine, University of Lisbon, Lisbon, Portugal
Martins M.:
Faculty of Medicine, University of Lisbon, Lisbon, Portugal
Borroni B.:
Neurology Unit, Department of Clinical and Experimental Sciences, Centre for Neurodegenerative Disorders, University of Brescia, Brescia, Italy
Padovani A.:
Neurology Unit, Department of Clinical and Experimental Sciences, Centre for Neurodegenerative Disorders, University of Brescia, Brescia, Italy
Almeida M.R.:
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Santana I.:
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Diehl-Schmid J.:
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
Alexopoulos P.:
Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
Clarimon J.:
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Lleó A.:
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Fortea J.:
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
Tsolaki M.:
3rd Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
Koutroumani M.:
Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece
Matej R.:
Department of Pathology, First Medical Faculty, Charles University, Prague, Czech Republic
Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic
De Deyn P.:
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium
Engelborghs S.:
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium
Cras P.:
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Department of Neurology, Antwerp University Hospital, Edegem, Belgium
Van Broeckhoven C.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Sleegers K.:
Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Rohan Z.:
Department of Pathology, First Medical Faculty, Charles University, Prague, Czech Republic
Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic
Institute of Pathology, Third Medical Faculty, Charles University, Prague, Czech Republic
All Open Access, Hybrid Gold
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