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 Madsen
  • Maria Kibæk
  • Xavier Roca
  • Ravi Sachidanandam
  • Adrian R. Krainer
  • Ernst Christensen
  • Robert D. Steiner
  • K. Michael Gibson
  • Thomas J. Corydon
  • Inga Knudsen
  • Ronald J.A. Wanders
  • Jos P.N. Ruiter
  • Niels Gregersen
  • Brage Storstein Andresen
Original Investigation

DOI: 10.1007/s00439-005-0070-4

Cite this article as:
Madsen, P.P., Kibæk, M., Roca, X. et al. Hum Genet (2006) 118: 680. doi:10.1007/s00439-005-0070-4

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) deficiencyIVS+3A>G mutation5′ splice site mutationExon skippingNewborn screening

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Pia Pinholt Madsen
    • 1
    • 2
  • Maria Kibæk
    • 3
  • Xavier Roca
    • 4
  • Ravi Sachidanandam
    • 4
  • Adrian R. Krainer
    • 4
  • Ernst Christensen
    • 5
  • Robert D. Steiner
    • 6
  • K. Michael Gibson
    • 6
  • Thomas J. Corydon
    • 2
  • Inga Knudsen
    • 1
  • Ronald J.A. Wanders
    • 7
  • Jos P.N. Ruiter
    • 7
  • Niels Gregersen
    • 1
  • Brage Storstein Andresen
    • 1
    • 2
  1. 1.Research Unit for Molecular MedicineAarhus University Hospital and Faculty of Health ScienceAarhusDenmark
  2. 2.Institute of Human GeneticsAarhus UniversityAarhusDenmark
  3. 3.Department of PediatricsOdense University HospitalOdenseDenmark
  4. 4.Cold Spring Harbor LaboratoryCold Spring HarborUSA
  5. 5.Department of Clinical GeneticsRigshospitaletCopenhagenDenmark
  6. 6.Departments of Molecular and Medical Genetics and Pediatrics, Biochemical Genetics LaboratoryOregon Health & Science UniversityPortlandUSA
  7. 7.Laboratory for Genetic Metabolic Diseases, Department of Clinical Chemistry and Pediatrics, Academic Medical CenterUniversity of AmsterdamAmsterdamthe Netherlands