title: P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms.
abstract: Cytochrome P450 oxidoreductase (POR) is required for metabolic reactions of steroid and drug metabolizing cytochrome P450 proteins located in endoplasmic reticulum. Mutations in POR cause a complex set of disorders resembling combined deficiencies of multiple steroid metabolizing enzymes. The P450 oxidoreductase deficiency (PORD) was first reported in patients with symptoms of defects in steroidogenic cytochrome P450 enzymes and ambiguous genitalia, and bone malformation features resembling Antley-Bixler syndrome. POR is now classified as a separate and rare form of congenital adrenal hyperplasia (CAH), which may cause disorder of sexual development (DSD). Since the initial description of PORD in 2004, a large number of POR mutations and polymorphisms have been described. In this report we have performed computational analysis of mutations and polymorphisms in POR linked to metabolism of steroids and xenobiotics and pathology of PORD from the reported cases. The mutations in POR that were identified in patients with disruption of steroidogenesis also have severe effects on cytochrome P450 proteins involved in metabolism of drugs. Different variations in POR show a range of diverse effects on different partner proteins that are often linked to the location of the particular variants. The variations in POR that cause defective binding of co-factors always have damaging effects on all partner proteins, while the mutations causing subtle structural changes may lead to altered interaction with partner proteins and the overall effect may be different for each individual partner. Computational analysis of available sequencing data and mutation analysis shows that Japanese (R457H), Caucasian (A287P) and Turkish (399-401) populations can be linked to unique founder mutations. Other mutations identified so far were identified as rare alleles or in single isolated reports. The common polymorphism of POR is the variant A503V which can be found in about 27% of alleles in general population but there are remarkable differences among different sub populations.
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University Children's Hospital Bern, and Department of Clinical Research, University of Bern, Switzerland.
authors.forename: Fabian Z
authors.initials: FZ
authors.lastname: Burkhard
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University Children's Hospital Bern, and Department of Clinical Research, University of Bern, Switzerland.
authors.forename: Shaheena
authors.initials: S
authors.lastname: Parween
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University Children's Hospital Bern, and Department of Clinical Research, University of Bern, Switzerland.
authors.forename: Sameer S
authors.initials: SS
authors.lastname: Udhane
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University Children's Hospital Bern, and Department of Clinical Research, University of Bern, Switzerland.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Flück
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics, University Children's Hospital Bern, and Department of Clinical Research, University of Bern, Switzerland. Electronic address: amit@pandeylab.org.
authors.forename: Amit V
authors.initials: AV
authors.lastname: Pandey
mesh_terms: D000483:Alleles; D000818:Animals; D001665:Binding Sites; D004252:DNA Mutational Analysis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D018703:Founder Effect; D014644:Genetic Variation; D006801:Humans; D021621:Imaging, Three-Dimensional; D007564:Japan; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency* / Q000235:genetics; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013256:Steroids / Q000378:metabolism*; D014421:Turkey; D044465:White People
chemical_list: D013256:Steroids; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D009251:NADPH-Ferrihemoprotein Reductase
keywords: Antley-Bixler syndrome; CYP17A1; Cytochrome P450 oxidoreductase; Disorders of sexual development; P450 oxidoreductase deficiency; PORD; Steroid metabolism