The ETFDH c.158A>G Variation Disrupts the Balanced Binding of ESE and ESS Proteins Causing Missplicing and Multiple acyl-CoA Dehydrogenation Deficiency
| Autor: | Olsen, Rikke K J, Brøner, Sabrina, Sabaratnam, Rugivan, Doktor, Thomas K, Andersen, Henriette S, Bruun, Gitte H, Gahrn, Birthe, Stenbroen, Vibeke, Olpin, Simon E, Dobbie, Angus, Gregersen, Niels, Andresen, Brage S |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Zdroj: | Olsen, R K J, Brøner, S, Sabaratnam, R, Doktor, T K, Andersen, H S, Bruun, G H, Gahrn, B, Stenbroen, V, Olpin, S E, Dobbie, A, Gregersen, N & Andresen, B S 2013, ' The ETFDH c.158A >G Variation Disrupts the Balanced Binding of ESE and ESS Proteins Causing Missplicing and Multiple acyl-CoA Dehydrogenation Deficiency ', Human Mutation . https://doi.org/10.1002/humu.22455 |
| DOI: | 10.1002/humu.22455 |
| Popis: | Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid and amino acid oxidation caused by defects of electron transfer flavoprotein (ETF) or its dehydrogenase (ETFDH). A clear relationship between genotype and phenotype makes genotyping of patients important not only diagnostically but also for prognosis and for assessment of treatment. In the present study we show that a predicted benign ETFDH missense variation (c.158A>G/p.Lys53Arg) in exon 2 causes exon skipping and degradation of ETFDH protein in patient samples. Using splicing reporter minigenes and RNA pull-down of nuclear proteins we show that the c.158A>G variation increases the strength of a preexisting exonic splicing silencer (ESS) motif UAGGGA. This ESS motif binds splice inhibitory hnRNP A1, hnRNP A2/B2 and hnRNP H proteins. Binding of these inhibitory proteins prevents binding of the positive splicing regulatory SRSF1 and SRSF5 proteins to nearby and overlapping exonic splicing enhancer (ESE) elements and this causes exon skipping. We further suggest that binding of hnRNP proteins to UAGGGA is increased by triggering synergistic hnRNP H binding to GGG triplets located up-stream and down-steam of the UAGGGA motif. A number of disease-causing exonic elements that induce exon skipping in other genes have a similar architecture as the one in ETFDH exon 2. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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