title: A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3.
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.
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands s.ferdinandusse@amc.nl.
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Jimenez-Sanchez
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Janet
authors.initials: J
authors.lastname: Koster
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Denis
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Carlo W
authors.initials: CW
authors.lastname: Van Roermund
authors.affiliation: 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.
authors.forename: Irma
authors.initials: I
authors.lastname: Silva-Zolezzi
authors.affiliation: Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Ann B
authors.initials: AB
authors.lastname: Moser
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Wouter F
authors.initials: WF
authors.lastname: Visser
authors.affiliation: Department of Pathology and.
authors.forename: Mine
authors.initials: M
authors.lastname: Gulluoglu
authors.affiliation: Department of Pediatric Gastrohepatology.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Durmaz
authors.affiliation: Department of Pediatric Nutrition and Metabolism, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey and.
authors.forename: Mubeccel
authors.initials: M
authors.lastname: Demirkol
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.affiliation: Department of Pediatric Nutrition and Metabolism, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey and.
authors.forename: Gülden
authors.initials: G
authors.lastname: Gökcay
authors.affiliation: Laboratory Genetic Metabolic Diseases, Department of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Valle
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism*
chemical_list: C063305:ABCD3 protein, human; D018528:ATP-Binding Cassette Transporters; C489271:Abcd3 protein, mouse; D001647:Bile Acids and Salts; D005227:Fatty Acids; C002844:pristanic acid