Antley-Bixler syndrome or POR deficiency?
Authors:
M. Tomková 1; C. C. Marohnic 2; A. Baxová 1; P. Martásek 1
Authors‘ workplace:
Klinika dětského a dorostového lékařství 1. LF UK a VFN, Praha
1; Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
2
Published in:
Čas. Lék. čes. 2008; 147: 261-265
Category:
Review Article
Overview
Antley-Bixler syndrome (ABS) is a rare congenital disorder characterized by numerous craniofacial, skeletal and, in some cases, urogenital abnormalities resulting from disordered steroidogenesis. Known genetic causes in sporadic cases of ABS include dominant mutations in the fibroblast growth factor 2 receptor gene (FGFR2). Recent research shows surprisingly that symptoms of Antley-Bixler syndrome, combined with disordered steroidogenesis and urogenital anomalies, are caused by mutations in the POR gene that encodes NADPH-cytochrome P450 oxidoreductase (CYPOR). CYPOR is a four domain-containing monomeric flavoprotein that contains two flavins, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), a binding site for NADPH, and the N-terminal sequence of 25 amino acids which determines the microsomal localization of the protein. CYPOR is the electron donor to microsomally localized cytochromes P450 that participate in xenobiotic metabolism and steroidogenesis. Mutations in the POR gene lead to apparent diminished activity of some P450 enzymes. Association of CYPOR with ABS discloses new facts about this disease and recent research shows that patients with ABS-like skeletal anomalies, but with mutations in the POR gene and disordered steroidogenesis, represent a new disorder called POR deficiency.
Key words:
Antley-Bixler syndrome, POR deficiency, NADPH-cytochrome P450 oxidoreductase, disordered steroidogenesis.
Sources
1. Antley, R. M., Bixler, D.: Trapezoidocephaly, midface hypoplasia and cartilage abnormalities with multiple synostoses and skeletal fractures. Birth Defects Orig. Art. Ser., 1975, 11, s. 397–401.
2. Adachi, M., Asakura, Y., Tachibana, K., Shackleton, C.: Abnormal steroidogenesis in three patients with Antley-Bixler syndrome: apparent decreased activity of 17alpha-hydroxylase, 17,20-lyase and 21-hydroxylase. Pediatr. Int., 2004, 46, s. 583–589.
3. Fukami, M., Horikawa, R., Nagai, T. et al.: 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. Endocr. Metab., 2005, 90, s. 414–426.
4. Williamson, L., Arlt, W., Shackleton, C. et al.: Linking Antley-Bixler syndrome and congenital adrenal hyperplasia: a novel case of P450 oxidoreductase deficiency. Am. J. Med. Genet., 2006, 140A, s. 1797–1803.
5. Hassell, S., Butler, M. G.: Antley-Bixler syndrome: report of a patient and review of literature. Clin. Genet., 1994, 46, s. 372–376.
6. Bottero, L., Cinalli, G., Labrune, P. et al.: Antley-Bixler syndrome: Description of two new cases and a review of the literature. Childs. Nerv. Syst., 1997, 13, s. 275–281.
7. Schinzel, A., Savoldelli, G., Briner, J. et al.: Antley-Bixler syndrome in sisters: a term newborn and a prenatally diagnosed fetus. Am. J. Med. Genet., 1983, 14, s. 139–147.
8. LeHeup, B. P., Masutti, J. P., Droulle, P., Tisserand, J.: The Antley-Bixler syndrome: report of two familial cases with severe renal and anal anomalies. Europ. J. Pediat., 1995, 154, s. 130–133.
9. Suzuki, K., Kanda, Y., Sugiyama, K. et al.: Antley-Bixler syndrome in a sister and brother. Jpn. J. Hum. Genet., 1987, 32, s. 247–252.
10. Yasui, Y., Yamaguchi, A., Itoh, Y. et al.: The first case of the Antley-Bixler syndrome with consanguinity in Japan. Jpn. J. Hum. Genet., 1983, 28, s. 215–220.
11. Feigin, E., Udassin, R., Seror, D. et al.: Antley-Bixler syndrome and esophageal atresia in a patient with trisomy 21. Clin. Genet., 1995, 47, s. 53–55.
12. Chun, K., Siegel-Bartelt, J., Chitayat, D. et al.: FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome. Am. J. Med. Genet., 1998, 77, s. 219–224.
13. Gorlin, R. J.: Patient described by Chun et al. may not present Antley-Bixler syndrome. (Letter). Am. J. Med. Genet., 1999, 83, s. 64.
14. Gripp, K. W., Zackai, E. H., Cohen, M. M., Jr.: Not Antley--Bixler syndrome. (Letter). Am. J. Med. Genet., 1999, 83, s. 65–66.
15. Tsai, F. J., Wu, J. Y., Yang, C. F., Tsai, C. H.: Further evidence that fibroblast growth factor receptor 2 mutations cause Antley-Bixler syndrome. Acta Paediatr., 2001, 90, s. 595–597.
16. Lee, B. E., Feinberg, M., Abraham J. J., Murthy, A. R.: Congenital malformation in an infant born to a woman treated with fluconazole. Pediatr. Infect. Dis. J., 1992, 11, s. 1062–1064.
17. Pursley, T. J., Blomquist, I. K., Abraham, J. et al.: Fluconazole-induced congenital anomalies in three infants. Clin. Infect. Dis., 1996, 22, s. 336–340.
18. Aleck, K. A., Bartley, D. L.: Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am. J. Med. Genet., 1997, 72, s. 253–256.
19. Jick, S. S.: Pregnancy outcomes after maternal exposure to fluconazole. Pharmacotherapy, 1999, 19, s. 221–222.
20. Reardon, W., Smith, A., Honour, J. W. et al.: Evidence for digenic inheritance in some cases of Antley-Bixler syndrome? J. Med. Genet., 2000, 37, s. 26–32.
21. Kelley, R. I., Kratz, L. E., Glaser, R. L. et al.: Abnormal sterol metabolism in a patient with Antley-Bixler syndrome and ambiguous genitalia. Am. J. Med. Genet., 2002, 110, s. 95–102.
22. Flück, C. E., Tajima, T., Pandey, A. V. et al.: Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat. Genet., 2004, 36, s. 228–230.
23. Adachi, M., Tachibana, K., Asakura, Y. et al.: Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome. Am. J. Med. Genet. A, 2004b, 128A, s. 333–339.
24. Huang, N., Pandey, A. V., Agrawal, V. et al.: Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am. J. Hum. Genet., 2005, 76, s. 729–749.
25. Arlt, W., Walker, E. A., Draper, N. et al.: Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet, 2004, 363, s. 2128–2135.
26. Homma, K., Hasegawa, T., Nagai, T. et al.: Urine Steroid Hormone Profile Analysis in Cytochrome P450 Oxidoreductase Deficiency: Implication for the Backdoor Pathway to Dihydrotestosterone. J. Clin. Endocrinol. Metab., 2006, 91, s. 2643–2649.
27. Hughes, A. L., Powell, D. W., Bard, M. et al.: Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes. Cell. Metab., 2007, 5, s. 143–149.
28. Schacter, B. A., Nelson, E. B., Marver, H. S., Masters, B. S.: Immunochemical evidence for an association of heme oxygenase with the microsomal electron transport system. J. Biol. Chem., 1972, 247, s. 3601–3607.
29. Ilan, Z., Ilan, R., Cinti, D. L.: Evidence for a new physiological role of hepatic NADPH:ferricytochrome (P-450) oxidoreductase. Direct electron input to the microsomal fatty acid chain elongation system. J. Biol. Chem., 1981, 256, s. 10066–10072.
30. Ono, T., Bloch, K.: Solubilization and partial characterization of rat liver squalene epoxidase. J. Biol. Chem., 1975, 250, s. 1571–1579.
31. Enoch, H. G., Strittmatter, P.: Cytochrome b5 reduction by NADPH-cytochrome P-450 reductase. J. Biol. Chem., 1979, 254, s. 8976–8981.
32. Horecker, B. L.: Triphosphopyridine nucleotide-cytochrome c reductase in liver. J. Biol. Chem., 1950, 183, s. 593–605.
33. Strittmatter, P., Velick, S. F.: The isolation and properties of microsomal cytochrome. J. Biol. Chem., 1956, 221, s. 253–264.
34. Williams, C. J., Kamin, H.: Microsomal triphosphopyridine nucleotide-cytochrome c reductase of liver. J. Biol. Chem., 1962, 237, s. 587–595.
35. Phillips, A. H., Langdon, R. G.: Hepatic triphosphopyridine nucleotide-cytochrome c reductase: isolation, characterization, and kinetic studies. J. Biol. Chem., 1962, 237, s. 2652–2660.
36. Iyanagi, T., Mason, H. S.: Some properties of hepatic reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase. Biochemistry, 1973, 12, s. 2297–2308.
37. Shephard, E.A., Phillips, I. R., Santisteban, I. et al.: Isolation of a human cytochrome P–450 reductase cDNA clone and localization of the corresponding gene to chromosome 7q11.2. Ann. Hum. Genet., 1989, 53, s. 291–301.
38. Wang, M., Roberts, D. L., Paschke, R. et al.: Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes. Proc. Natl. Acad. Sci. USA., 1997, 94, s. 8411–8416.
39. Shen, A. L., O’Leary, K. A., Kasper, C. B.: Association of multiple developmental defects and embryonic lethality with loss of microsomal NADPH-cytochrome P450 oxidoreductase. J. Biol. Chem., 2002, 277, s. 6536–6541.
40. Marohnic, C. C., Panda, S. P., Martásek, P., Masters, B. S.: Diminished FAD binding in the Y459H & V492E Antley--Bixler syndrome mutants of human cytochrome P450 reductase. J. Biol. Chem., 2006, 281, s. 35975–35982.
41. Ribes, V., Fraulob, V., Petkovich, M., Dolle, P.: The oxidizing enzyme CYP26A1 tightly regulates the availability of retinoic acid in the gastrulating mouse embryo to ensure proper head development and vasculogenesis. Dev. Dyn., 2007, 236, s. 644–653.
42. Herman, G. E.: Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes. Hum. Mol. Genet., 2003, 12, s. R75–R88.
43. Debeljak, N., Fink, M., Rozman, D.: Many facets of mammalian lanosterol 14alpha-demethylase from the evolutionarily conserved cytochrome P450 family CYP51. Arch. Biochem. Biophys., 2003, 409, s. 159–171.
44. Miller, W. L., Huang, N., Pandey, A. V. et al.: P450 oxidoreductase deficiency: a new disorder of steroidogenesis. Ann. N. Y. Acad. Sci., 2005, 1061, s. 100–108.
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