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The ETFDH c.158 A > G Variation Disrupts the Balanced Interplay of ESE‐ and ESS ‐Binding Proteins thereby Causing Missplicing and Multiple Acyl‐ C o A Dehydrogenation Deficiency
Author(s) -
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.
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22455
Subject(s) - exon , biology , rna splicing , exon skipping , sr protein , rna binding protein , exonic splicing enhancer , microbiology and biotechnology , genetics , intron , alternative splicing , enhancer , gene , rna , transcription factor
Multiple acyl‐ C o A dehydrogenation deficiency 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.158 A > G /p. L ys53 A rg) 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.158 A > G variation increases the strength of a preexisting exonic splicing silencer ( ESS ) motif UAGGGA . This ESS motif binds splice inhibitory hn RNP A 1, hn RNP A 2/ B 1, and hn RNP H proteins. Binding of these inhibitory proteins prevents binding of the positive splicing regulatory SRSF 1 and SRSF 5 proteins to nearby and overlapping exonic splicing enhancer elements and this causes exon skipping. We further suggest that binding of hn RNP proteins to UAGGGA is increased by triggering synergistic hn RNP H binding to GGG triplets located upstream and downsteam 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.