Publicaciones científicas
Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease
Arne De Roeck 1 2 , Tobi Van den Bossche 1 2 3 4 , Julie van der Zee 1 2 , Jan Verheijen 1 2 , Wouter De Coster 1 2 , Jasper Van Dongen 1 2 , Lubina Dillen 1 2 , Yalda Baradaran-Heravi 1 2 , Bavo Heeman 1 2 , Raquel Sanchez-Valle 5 , Albert Lladó 5 , Benedetta Nacmias 6 , Sandro Sorbi 6 7 , Ellen Gelpi 8 , Oriol Grau-Rivera 8 , Estrella Gómez-Tortosa 9 , Pau Pastor 10 11 , Sara Ortega-Cubero 11 , Maria A Pastor 11 12 13 , Caroline Graff 14 15 , Håkan Thonberg 14 15 , Luisa Benussi 16 , Roberta Ghidoni 16 , Giuliano Binetti 16 17 , Alexandre de Mendonça 18 , Madalena Martins 18 , Barbara Borroni 19 , Alessandro Padovani 19 , Maria Rosário Almeida 20 , Isabel Santana 20 , Janine Diehl-Schmid 21 , Panagiotis Alexopoulos 21 , Jordi Clarimon 11 22 , Alberto Lleó 11 22 , Juan Fortea 11 22 , Magda Tsolaki 23 , Maria Koutroumani 24 , Radoslav Matěj 25 26 , Zdenek Rohan 25 26 27 , Peter De Deyn 2 4 , Sebastiaan Engelborghs 2 4 , Patrick Cras 2 3 , Christine Van Broeckhoven 28 29 , Kristel Sleegers 30 31 , European Early-Onset Dementia (EU EOD) consortium
Abstract
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.
CITA DEL ARTÍCULO Acta Neuropathol. 2017 Sep;134(3):475-487. doi: 10.1007/s00401-017-1714-x. Epub 2017 Apr 27.