Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease

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.

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease

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 prot...

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Detalhes bibliográficos
Autores:	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.
Formato:	artículo
Estado:	Versión publicada
Fecha de publicación:	2017
País:	España
Recursos:	Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:	r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:	oai:iibsantpau.fundanetsuite.com:p10497
Acesso em linha:	https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10497 http://ddd.uab.cat/record/186219
Access Level:	acceso abierto
Palavra-chave:	ABC transporter ABC transporter A7 apolipoprotein E4 unclassified drug ABCA7 protein, human adult aged alternative RNA splicing Alzheimer disease amino terminal sequence Article cohort analysis controlled study disease severity DNA sequence female frameshift mutation gene frequency gene linkage disequilibrium gene mutation genetic code haplotype human major clinical study male missense mutation next generation sequencing nonsense mediated mRNA decay nonsense mutation prevalence priority journal protein expression risk reduction single nucleotide polymorphism genetic association study genetic predisposition genetics middle aged mutation onset age Adult Age of Onset Aged Alzheimer Disease ATP-Binding Cassette Transporters Female Genetic Association Studies Genetic Predisposition to Disease Humans Male Middle Aged Mutation Polymorphism, Single Nucleotide

Descrição
Resumo:	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).

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease

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