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      Genetic and clinical features of p450 oxidoreductase deficiency.

      1 ,
      Hormone research
      S. Karger AG

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          Abstract

          P450 oxidoreductase (POR) deficiency is an autosomal recessive disorder of steroidogenesis with multiple clinical manifestations. POR is the electron donor for all microsomal P450 enzymes, including the three steroidogenic enzymes P450c17 (17alpha-hydroxylase/17,20-lyase), P450c21 (21-hydroxylase), and P450aro (aromatase). Since the first description of POR mutations in 2004, about 50 patients have been reported. Serum steroid profiles indicate partial deficiencies in 21-hydroxylase, 17alpha-hydroxylase and 17,20-lyase. The 17-OH progesterone levels are elevated, as in 21-hydroxylase deficiency, while androgen levels are low; cortisol may be normal but is poorly responsive to adrenocorticotropic hormone. Most patients also have associated skeletal malfor- mations (craniosynostosis, radio-ulnar synostosis, midface hypoplasia, bowed femora) termed Antley-Bixler syndrome. Antley-Bixler syndrome with normal steroidogenesis is caused by autosomal dominant gain-of-function mutations in fibroblast growth factor receptor 2. Males with POR deficiency are often undervirilized, while females can be virilized. The prognosis for patients with POR deficiency appears to depend on the severity of the bony malformations and their timely treatment. The potential impact of POR mutations on drug metabolism by other hepatic P450 enzymes requires further investigation. Given the varied physical and biochemical phenotype of POR deficiency and the risk of adrenal insufficiency, clinicians should be alert to this potential diagnosis.

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          Most cited references49

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          Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.

          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.
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            Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.

            Crouzon syndrome is an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis) and maps to chromosome 10q25-q26. We now present evidence that mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause Crouzon syndrome. We found SSCP variations in the B exon of FGFR2 in nine unrelated affected individuals as well as complete cosegregation between SSCP variation and disease in three unrelated multigenerational families. In four sporadic cases, the normal parents did not have SSCP variation. Finally, direct sequencing has revealed specific mutations in the B exon in all nine sporadic and familial cases, including replacement of a cysteine in an immunoglobulin-like domain in five patients.
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              Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer.

              In the biosynthesis of steroid hormones, P450c17 is the single enzyme that catalyzes both the 17alpha-hydroxylation of 21-carbon steroids and the 17,20-lyase activity that cleaves the C17-C20 bond to produce C19 sex steroids. Cytochrome b5 augments the 17,20-lyase activity of cytochrome P450c17 in vitro, but this has not been demonstrated in membranes, and the mechanism of this action is unknown. We expressed human P450c17, human P450-oxidoreductase (OR), and/or human cytochrome b5 in Saccharomyces cerevisiae and analyzed the 17alpha-hydroxylase and 17,20-lyase activities of the resulting yeast microsomes. Yeast expressing only P450c17 have 17alpha-hydroxylase and trace 17,20-lyase activities toward both Delta4 and Delta5 steroids. Coexpression of human OR with P450c17 increases the Vmax of both the 17alpha-hydroxylase and 17,20-lyase reactions 5-fold; coexpression of human b5 with P450c17 also increases the Vmax of the 17,20-lyase reactions but not of the 17alpha-hydroxylase reactions. Simultaneous expression of human b5 with P450c17 and OR, or addition of purified human b5 to microsomes from yeast coexpressing human P450c17 and OR, further increases the Vmax of the 17,20-lyase reaction without altering 17alpha-hydroxylase activity. Genetically engineered yeast and mixing experiments demonstrate that OR is both necessary and sufficient for microsomal 17,20-lyase activity. Addition of purified human holo-b5, apo-b5, or cytochrome c to microsomes containing both human P450c17 and OR demonstrate that the stimulatory action of b5 does not require electron transfer from b5 to P450c17. These data suggest that human b5 acts principally as an allosteric effector that interacts primarily with the P450c17.OR complex to stimulate 17, 20-lyase activity.
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                Author and article information

                Journal
                Horm. Res.
                Hormone research
                S. Karger AG
                1423-0046
                0301-0163
                2008
                : 69
                : 5
                Affiliations
                [1 ] Division of Endocrinology, Department of Paediatrics, IWK Health Centre, Dalhousie University, Halifax, N.S., Canada. rrscott@dal.ca
                Article
                000114857
                10.1159/000114857
                18259105
                938a73e3-7355-451e-a2f2-4c851cd163b4
                History

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