A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3

  • Hum Mol Genet. 2015 Jan 15;24(2):361-70. doi: 10.1093/hmg/ddu448.
Sacha Ferdinandusse  1 ,  Gerardo Jimenez-Sanchez  2 ,  Janet Koster  3 ,  Simone Denis  3 ,  Carlo W Van Roermund  3 ,  Irma Silva-Zolezzi  4 ,  Ann B Moser  5 ,  Wouter F Visser  3 ,  Mine Gulluoglu  6 ,  Ozlem Durmaz  7 ,  Mubeccel Demirkol  8 ,  Hans R Waterham  3 ,  Gülden Gökcay  8 ,  Ronald J A Wanders  3 ,  David Valle  2
Affiliations
  • 1. Laboratory Genetic Metabolic Diseases, Department of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands [email protected].
  • 2. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
  • 3. Laboratory Genetic Metabolic Diseases, Department of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
  • 4. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA Programa de Posgrado en Biomedicina Molecular. Cinvestav-IPN, Av. IPN 2508, Col. Zacatenco, CP 07360, México, D.F., Mexico.
  • 5. Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 6. Department of Pathology and.
  • 7. Department of Pediatric Gastrohepatology.
  • 8. Department of Pediatric Nutrition and Metabolism, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey and.
PMID: 25168382 DOI: 10.1093/hmg/ddu448
Abstract

ABCD3 is one of three ATP-binding cassette (ABC) transporters present in the peroxisomal membrane catalyzing ATP-dependent transport of substrates for metabolic pathways localized in peroxisomes. So far, the precise function of ABCD3 is not known. Here, we report the identification of the first patient with a defect of ABCD3. The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma. Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes. Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced. Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 Amino acids (p.Y635NfsX1). Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation. To corroborate our findings in the patient, we studied a previously generated Abcd3 knockout mouse model. Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading. In addition, analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice. Thus, both in the patient and in Abcd3-/- mice, there was evidence of a bile acid biosynthesis defect. In conclusion, our studies show that ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids into the peroxisome and that this is a crucial step in bile acid biosynthesis.