Original Investigation

Human Genetics

, Volume 118, Issue 6, pp 680-690

Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping

  • Pia Pinholt MadsenAffiliated withResearch Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health ScienceInstitute of Human Genetics, Aarhus University
  • , Maria KibækAffiliated withDepartment of Pediatrics, Odense University Hospital
  • , Xavier RocaAffiliated withCold Spring Harbor Laboratory
  • , Ravi SachidanandamAffiliated withCold Spring Harbor Laboratory
  • , Adrian R. KrainerAffiliated withCold Spring Harbor Laboratory
  • , Ernst ChristensenAffiliated withDepartment of Clinical Genetics, Rigshospitalet
  • , Robert D. SteinerAffiliated withDepartments of Molecular and Medical Genetics and Pediatrics, Biochemical Genetics Laboratory, Oregon Health & Science University
  • , K. Michael GibsonAffiliated withDepartments of Molecular and Medical Genetics and Pediatrics, Biochemical Genetics Laboratory, Oregon Health & Science University
  • , Thomas J. CorydonAffiliated withInstitute of Human Genetics, Aarhus University
    • , Inga KnudsenAffiliated withResearch Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Science
    • , Ronald J.A. WandersAffiliated withLaboratory for Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam
    • , Jos P.N. RuiterAffiliated withLaboratory for Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam
    • , Niels GregersenAffiliated withResearch Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Science
    • , Brage Storstein AndresenAffiliated withResearch Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health ScienceInstitute of Human Genetics, Aarhus University Email author 

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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.

Keywords

SBCAD (ACADSB) deficiency IVS+3A>G mutation 5′ splice site mutation Exon skipping Newborn screening