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Cytochrome P450 Reductase OKDB#: 2412
 Symbols: POR Species: human
 Synonyms: DISORDERED STEROIDOGENESIS, ISOLATED, INCLUDED  Locus: 7q11.2 in Homo sapiens


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General Comment Shephard et al. (1989) isolated and sequenced cDNA clones that code for rat and human NADPH-dependent cytochrome P-450 reductase. Southern blot analysis of DNA isolated from a panel of 8 independent human-rodent somatic cell hybrids indicated that cytochrome P-450 reductase is encoded by a single gene located on 7pter-q22.

General function Enzyme
Comment
Cellular localization Mitochondrial
Comment
Ovarian function Steroid metabolism, Luteinization
Comment P450 oxidoreductase deficiency: a new disorder of steroidogenesis with multiple clinical manifestations. Miller WL. 2004 . Combined partial deficiency of 17alpha-hydroxylase and 21-hydroxylase is well-described, but patients' genes for these enzymes lack mutations. Recent work has identified mutations in the gene for P450 oxidoreductase (POR) in such patients. POR-deficient individuals have a broad range of disorders, from infants with congenital malformations to women with the polycysic ovary syndrome. POR transfers electrons to all microsomal P450 enzymes: its deficiency affects steroidogenesis, drug metabolism and other processes.
Expression regulated by FSH, LH
Comment Gene expression decreased. Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression. Agca C et al. The LH surge initiates the luteinization of preovulatory follicles and causes hormonal and structural changes that ultimately lead to ovulation and the formation of corpora lutea. The objective of the study was to examine gene expression in ovarian follicles (n = 11) collected from pigs (Sus scrofa domestica) approaching estrus (estrogenic preovulatory follicle; n = 6 follicles from two sows) and in ovarian follicles collected from pigs on the second day of estrus (preovulatory follicles that were luteinized but had not ovulated; n = 5 follicles from two sows). The follicular status within each follicle was confirmed by follicular fluid analyses of estradiol and progesterone ratios. Microarrays were made from expressed sequence tags that were isolated from cDNA libraries of porcine ovary. Gene expression was measured by hybridization of fluorescently labeled cDNA (preovulatory estrogenic or -luteinized) to the microarray. Microarray analyses detected 107 and 43 genes whose expression was decreased or increased (respectively) during the transition from preovulatory estrogenic to -luteinized (P<0.01). Cells within preovulatory estrogenic follicles had a gene-expression profile of proliferative and metabolically active cells that were responding to oxidative stress. Cells within preovulatory luteinized follicles had a gene-expression profile of nonproliferative and migratory cells with angiogenic properties. Approximately, 40% of the discovered genes had unknown function.
Ovarian localization Granulosa, Theca, Luteal cells
Comment
Follicle stages Secondary, Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
Mutations 2 mutations

Species: human
Mutation name: None
type: naturally occurring
fertility: infertile - ovarian defect
Comment: Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome Fluck CE, et al . Deficient activities of multiple steroidogenic enzymes have been reported without and with Antley-Bixler syndrome (ABS), but mutations of corresponding cytochrome P450 enzymes have not been found. We identified mutations in POR, encoding P450 oxidoreductase, the obligate electron donor for these enzymes, in a woman with amenorrhea and three children with ABS, even though knock-out of POR is embryonically lethal in mice. Mutations of POR also affect drug-metabolizing P450 enzymes, explaining the association of ABS with maternal fluconazole ingestion.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Transgenic Mice with a Hypomorphic NADPH-Cytochrome P450 Reductase Gene: Effects on Development, Reproduction, and Microsomal Cytochrome P450 Wu L, et al . A mouse model with a hypomorphic NADPH-cytochrome P450 reductase (Cpr) gene (designated Cpr(low) allele) was generated and characterized in this study. The Cpr gene in these mice was disrupted by the insertion of a neo gene in intron 15, which led to 74%-95% decreases in CPR expression in all tissues examined, including olfactory mucosa, adrenal gland, brain, testis, ovary, lung, kidney, liver, and heart. In the liver, a pattern of pericentral distribution of CPR protein was preserved in the Cpr(low/low) mice, despite an overall reduction in CPR expression. Genotype distribution in F2 pups indicated limited embryonic lethality associated with the Cpr(low) allele, a finding that confirms the role of CPR-dependent enzymes in development. Adult male homozygotes had decreased body weight, and decreased heart, lung, and kidney weights, whereas homozygous Cpr(low) females, which had increased serum testosterone and progesterone, and decreased copulatory activities, were infertile. Furthermore, adult Cpr(low/low) mice had decreased plasma cholesterol, and some mice developed mild centrilobular hepatic lipidosis. In addition, despite apparently compensatory increases in total microsomal cytochrome P450 content in the liver and kidney, the decreases in CPR expression were accompanied by reductions in systemic clearance of pentobarbital, as well as in hepatic microsomal metabolism of acetaminophen and testosterone. These phenotypes illustrate the potential impact of a globally decreased CPR activity in human adults, and this novel knock-in mouse model provides a unique opportunity for further explorations of the in vivo roles of CPR and CPR-dependent enzymes.

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Links
OMIM (Online Mendelian Inheritance in Man: an excellent source of general gene description and genetic information.)
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created: March 6, 2004, 7:10 a.m. by: hsueh   email:
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last update: July 20, 2006, 10:30 a.m. by: Alex    email:



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