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 journalArticle

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 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
Volume24
Issue number2
DOIs
StatePublished - Jan 15 2015

Fingerprint

Bile Acids and Salts
Peroxisomes
Liver Diseases
Fatty Acids
Phytanic Acid
Phytol
ATP-Binding Cassette Transporters
Metabolic Networks and Pathways
Protein C
Knockout Mice
Bile
Liver Transplantation
Intestines
Fibroblasts
Adenosine Triphosphate
Transplantation
Skin
Membranes
Liver
DNA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology
  • Medicine(all)

Cite this

Ferdinandusse, S., Jimenez-Sanchez, G., Koster, J., Denis, S., Van Roermund, C. W., Silva-Zolezzi, I., ... Valle, D. (2015). A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3. Human Molecular Genetics, 24(2), 361-370. [ddu448]. https://doi.org/10.1093/hmg/ddu448

A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3. / Ferdinandusse, Sacha; Jimenez-Sanchez, Gerardo; Koster, Janet; Denis, Simone; Van Roermund, Carlo W.; Silva-Zolezzi, Irma; Moser, Ann B.; Visser, Wouter F.; Gulluoglu, Mine; Durmaz, Ozlem; Demirkol, Mubeccel; Waterham, Hans R.; Gökcay, Gülden; Wanders, Ronald J A; Valle, David.

In: Human Molecular Genetics, Vol. 24, No. 2, ddu448, 15.01.2015, p. 361-370.

Research output: Contribution to journalArticle

Ferdinandusse, S, Jimenez-Sanchez, G, Koster, J, Denis, S, Van Roermund, CW, Silva-Zolezzi, I, Moser, AB, Visser, WF, Gulluoglu, M, Durmaz, O, Demirkol, M, Waterham, HR, Gökcay, G, Wanders, RJA & Valle, D 2015, 'A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3', Human Molecular Genetics, vol. 24, no. 2, ddu448, pp. 361-370. https://doi.org/10.1093/hmg/ddu448
Ferdinandusse S, Jimenez-Sanchez G, Koster J, Denis S, Van Roermund CW, Silva-Zolezzi I et al. A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3. Human Molecular Genetics. 2015 Jan 15;24(2):361-370. ddu448. https://doi.org/10.1093/hmg/ddu448
Ferdinandusse, Sacha ; Jimenez-Sanchez, Gerardo ; Koster, Janet ; Denis, Simone ; Van Roermund, Carlo W. ; Silva-Zolezzi, Irma ; Moser, Ann B. ; Visser, Wouter F. ; Gulluoglu, Mine ; Durmaz, Ozlem ; Demirkol, Mubeccel ; Waterham, Hans R. ; Gökcay, Gülden ; Wanders, Ronald J A ; Valle, David. / A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 2. pp. 361-370.
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