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

Sacha Ferdinandusse, Gerardo Jimenez-Sanchez, Janet Koster, Simone Denis, Carlo W. Van Roermund, Irma Silva-Zolezzi, Ann B. Moser, Wouter F. Visser, Mine Gulluoglu, Ozlem Durmaz, Mubeccel Demirkol, Hans R. Waterham, Gülden Gökcay, Ronald J.A. Wanders, David Valle

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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 ahomozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24aminoacids (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.

Original languageEnglish (US)
Article numberddu448
Pages (from-to)361-370
Number of pages10
JournalHuman molecular genetics
Issue number2
StatePublished - Jan 15 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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