Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping |
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| Authors: | Pia Pinholt Madsen Maria Kibæk Xavier Roca Ravi Sachidanandam Adrian R Krainer Ernst Christensen Robert D Steiner K Michael Gibson Thomas J Corydon Inga Knudsen Ronald JA Wanders Jos PN Ruiter Niels Gregersen Brage Storstein Andresen |
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| Institution: | (1) Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Science, Skejby Sygehus, Aarhus, Denmark;(2) Institute of Human Genetics, Aarhus University, Aarhus, Denmark;(3) Department of Pediatrics, Odense University Hospital, Odense, Denmark;(4) Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA;(5) Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark;(6) Departments of Molecular and Medical Genetics and Pediatrics, Biochemical Genetics Laboratory, Oregon Health & Science University, Portland, Oregon, USA;(7) Laboratory for Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands |
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| Abstract: | Short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) is an autosomal recessive disorder of l-isoleucine catabolism. Little is known about the clinical presentation associated with this enzyme defect, as it has been
reported in only a limited number of patients. Because the presence of C5-carnitine in blood may indicate SBCADD, the disorder
may be detected by MS/MS-based routine newborn screening. It is, therefore, important to gain more knowledge about the clinical
presentation and the mutational spectrum of SBCADD. In the present study, we have studied two unrelated families with SBCADD,
both with seizures and psychomotor delay as the main clinical features. One family illustrates the fact that affected individuals
may also remain asymptomatic. In addition, the normal level of newborn blood spot C5-acylcarnitine in one patient underscores
the fact that newborn screening by MS/MS currently lacks sensitivity in detecting SBCADD. Until now, seven mutations in the SBCAD gene have been reported, but only three have been tested experimentally. Here, we identify and characterize an IVS3+3A>G
mutation (c.303+3A>G) in the SBCAD gene, and provide evidence that this mutation is disease-causing in both families. Using a minigene approach, we show that
the IVS3+3A>G mutation causes exon 3 skipping, despite the fact that it does not appear to disrupt the consensus sequence
of the 5′ splice site. Based on these results and numerous literature examples, we suggest that this type of mutation (IVS+3A>G)
induces missplicing only when in the context of non-consensus (weak) 5′ splice sites. Statistical analysis of the sequences
shows that the wild-type versions of 5′ splice sites in which +3A>G mutations cause exon skipping and disease are weaker on
average than a random set of 5′ splice sites. This finding is relevant to the interpretation of the functional consequences
of this type of mutation in other disease genes. |
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| Keywords: | SBCAD (ACADSB) deficiency IVS+3A> G mutation 5′ splice site mutation Exon skipping Newborn screening |
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