title: CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids.
abstract: X-linked adrenoleukodystrophy (ALD) is a severe neurodegenerative disorder caused by the accumulation of very long-chain fatty acids (VLCFA) due to mutations in the ABCD1 gene. The phenotypic spectrum ranges from a fatal cerebral demyelinating disease in childhood (cerebral ALD) to a progressive myelopathy without cerebral involvement in adulthood (adrenomyeloneuropathy). Because ABCD1 mutations have no predictive value with respect to clinical outcome a role for modifier genes was postulated. We report that the CYP4F2 polymorphism rs2108622 increases the risk of developing cerebral ALD in Caucasian patients. The rs2108622 polymorphism (c.1297G>A) results in an amino acid substitution valine for methionine at position 433 (p.V433M). Using cellular models of VLCFA accumulation, we show that p.V433M decreases the conversion of VLCFA into very long-chain dicarboxylic acids by ω-oxidation, a potential escape route for the deficient peroxisomal β-oxidation of VLCFA in ALD. Although p.V433M does not affect the catalytic activity of CYP4F2 it reduces CYP4F2 protein levels markedly. These findings open perspectives for therapeutic interventions in a disease with currently limited treatment options.
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: van Engen
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Ofman
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Inge M E
authors.initials: IM
authors.lastname: Dijkstra
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Tessa Jacobs
authors.initials: TJ
authors.lastname: van Goethem
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Eveline
authors.initials: E
authors.lastname: Verheij
authors.affiliation: INSERM U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris-Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Varin
authors.affiliation: INSERM U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris-Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments 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: INSERM U986, Le Kremlin-Bicêtre, Paris, France; Faculté de Médecine, Université Paris-Sud, Assistance Publique des Hôpitaux de Paris, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.affiliation: Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: s.kemp@amc.uva.nl.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
authors.affiliation: INSERM U986, Le Kremlin-Bicêtre, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Barbier
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1 / Q000235:genetics / Q000378:metabolism; D000326:Adrenoleukodystrophy / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000072470:Cytochrome P450 Family 4 / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D005227:Fatty Acids; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human
keywords: Adrenoleukodystrophy; Cytochrome P450; Dicarboxylic acids; Modifier gene; Omega-oxidation; Peroxisomes