| Structural highlights
Disease
[NCPR_HUMAN] Defects in POR are the cause of Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1) [MIM:201750]. A disease characterized by the association of Antley-Bixler syndrome with steroidogenesis defects and abnormal genitalia. Antley-Bixler syndrome is characterized by craniosynostosis, radiohumeral synostosis present from the perinatal period, midface hypoplasia, choanal stenosis or atresia, femoral bowing and multiple joint contractures.[1] [2] [3] Defects in POR are the cause of disordered steroidogenesis due to cytochrome P450 oxidoreductase deficiency (DISPORD) [MIM:613571]. A disorder resulting in a rare variant of congenital adrenal hyperplasia, with apparent combined P450C17 and P450C21 deficiency and accumulation of steroid metabolites. Affected girls are born with ambiguous genitalia, but their circulating androgens are low and virilization does not progress. Conversely, affected boys are sometimes born undermasculinized. Boys and girls can present with bone malformations, in some cases resembling the pattern seen in patients with Antley-Bixler syndrome.[4] [5]
Function
[NCPR_HUMAN] This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes. It can also provide electron transfer to heme oxygenase and cytochrome B5.
Publication Abstract from PubMed
Human NADPH-cytochrome P450 oxidoreductase (POR) gene mutations are associated with severe skeletal deformities and disordered steroidogenesis. The human POR mutation A287P presents with disordered sexual development and skeletal malformations. Difficult recombinant expression and purification of this POR mutant suggested that the protein was less stable than WT. The activities of CYPs 17A1, 19A1 and 21A2, critical in steroidogenesis, were similar using our purified, full-length, unmodified A287P or WT POR, as were those of several xenobiotic-metabolizing CYPs, indicating that the A287P protein is functionally competent in vitro, despite its functionally deficient phenotypic behavior in vivo. Differential scanning calorimetry (DSC) and limited trypsinolysis studies revealed a relatively unstable A287P compared to WT protein, leading to the hypothesis that the syndrome observed in vivo results from altered POR protein stability. The crystal structures of the soluble domains of WT and A287P reveal only subtle differences between them, but these differences are consistent with the DSC results as well as the differential susceptibility of A287P and WT observed with trypsinolysis. The relative in vivo stabilities of WT and A287P proteins were also examined in an osteoblast cell line by treatment with cycloheximide, a protein synthesis inhibitor, showing that the level of A287P protein post-inhibition is lower than WT and suggesting that A287P may be degraded at a higher rate. Current studies demonstrate that, unlike previously described mutations, A287P causes POR deficiency disorder due to conformational instability leading to proteolytic susceptibility in vivo, rather than through an inherent flavin-binding defect.
Instability of the Human Cytochrome P450 Reductase A287P Variant Is the Major Contributor to its Antley-Bixler Syndrome-Like Phenotype.,McCammon KM, Panda SP, Xia C, Kim JP, Moutinho D, Kranendonk M, Auchus RJ, Lafer EM, Ghosh D, Martasek P, Kar R, Masters BS, Roman LJ J Biol Chem. 2016 Aug 5. pii: jbc.M116.716019. PMID:27496950[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Adachi M, Tachibana K, Asakura Y, Yamamoto T, Hanaki K, Oka A. Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome. Am J Med Genet A. 2004 Aug 1;128A(4):333-9. PMID:15264278 doi:10.1002/ajmg.a.30169
- ↑ Fukami M, Horikawa R, Nagai T, Tanaka T, Naiki Y, Sato N, Okuyama T, Nakai H, Soneda S, Tachibana K, Matsuo N, Sato S, Homma K, Nishimura G, Hasegawa T, Ogata T. Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. J Clin Endocrinol Metab. 2005 Jan;90(1):414-26. Epub 2004 Oct 13. PMID:15483095 doi:jc.2004-0810
- ↑ Fluck CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonca BB, Fujieda K, Miller WL. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet. 2004 Mar;36(3):228-30. Epub 2004 Feb 1. PMID:14758361 doi:10.1038/ng1300
- ↑ Fluck CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonca BB, Fujieda K, Miller WL. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet. 2004 Mar;36(3):228-30. Epub 2004 Feb 1. PMID:14758361 doi:10.1038/ng1300
- ↑ Arlt W, Walker EA, Draper N, Ivison HE, Ride JP, Hammer F, Chalder SM, Borucka-Mankiewicz M, Hauffa BP, Malunowicz EM, Stewart PM, Shackleton CH. Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet. 2004 Jun 26;363(9427):2128-35. PMID:15220035 doi:10.1016/S0140-6736(04)16503-3
- ↑ McCammon KM, Panda SP, Xia C, Kim JP, Moutinho D, Kranendonk M, Auchus RJ, Lafer EM, Ghosh D, Martasek P, Kar R, Masters BS, Roman LJ. Instability of the Human Cytochrome P450 Reductase A287P Variant Is the Major Contributor to its Antley-Bixler Syndrome-Like Phenotype. J Biol Chem. 2016 Aug 5. pii: jbc.M116.716019. PMID:27496950 doi:http://dx.doi.org/10.1074/jbc.M116.716019
|
