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Gene Review

CYP21A2  -  cytochrome P450, family 21, subfamily A,...

Homo sapiens

Synonyms: 21-OHase, CA21H, CAH1, CPS1, CYP21, ...
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Disease relevance of CYP21A2


Psychiatry related information on CYP21A2


High impact information on CYP21A2

  • We describe a new contiguous-gene syndrome, involving the CYP21B and TNX genes, that results in 21-hydroxylase deficiency and a connective-tissue disorder consisting of skin and joint hyperextensibility, vascular fragility and poor wound healing [7].
  • DNA sequence analysis suggests that the mutation arose by a microconversion event involving exchange of up to 390 nucleotides between maternal CYP21A and CYP21B genes [8].
  • Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a disorder of cortisol and aldosterone biosynthesis that results from mutations in the CYP21 gene encoding the adrenal 21-hydroxylase P-450c21 [9].
  • We measured plasma and urinary levels of adrenal hormones, plasma renin activity, and sodium balance longitudinally in the patient and four other patients in whom adrenal hyperplasia had been diagnosed in infancy and in whom DNA analysis had predicted a complete absence of functional P-450c21 [9].
  • Samples from eight patients with nonclassic 21-hydroxylase deficiency who had the haplotype HLA-B14,DR1 contained a hybridizing fragment 3700 base pairs long, indicating the presence of the valine-281 mutation in the CYP21B gene [10].

Chemical compound and disease context of CYP21A2


Biological context of CYP21A2

  • Since it is unlikely that the term 'large-scale gene conversion' describes a mechanism that actually occurs between the CYP21A2 and CYP21A1P genes, we propose the discontinuation of that terminology [2].
  • The main cause for the mutation of the CYP21A2 (c21B) gene is conversion of its nucleotide sequence to the neighboring homologous but nonfunctional c21A gene [13].
  • Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes [1].
  • Contemporary mutation-detection protocols based on the polymerase chain reaction often depend on the assumption that no more than one CYP21A2 gene is present on each chromosome 6 [1].
  • The classical and nonclassical phenotypes of 21-hydroxylase deficiency represent a continuous spectrum of the impairment of 21-hydroxylase activity due to mutations between the CYP21A2 gene [16].

Anatomical context of CYP21A2


Associations of CYP21A2 with chemical compounds

  • Blood cholesterol was grossly normal, and endocrine studies revealed defective CYP17A1 and CYP21A2 activities [22].
  • RESULTS: In the PORD patients, pregnanediol, pregnanetriolone, and pregnanetriol were obviously elevated, and the urine steroid ratios reflecting CYP17A1 and CYP21A2 activities were decreased throughout the examined ages [23].
  • Genetic analysis revealed that the girl was compound heterozygote for a previously reported Q318X mutation in exon 8 and a novel insertion of an adenine between nucleotides 962 and 963 in exon 4 of the CYP21A2 gene [24].
  • CONCLUSIONS: We established a non-radioactive (biotin) Southern blot/hybridization methodology for CYP21A2 large rearrangements with good results [25].
  • Our results show that there is a very high frequency (33%) of 21-hydroxylase deficiency haplotypes where functional CYP21B gene sequence has been removed as a consequence of CYP21 + C4 gene deletion while several haplotypes show evidence of gene addition [26].
  • K121 is located on helix C in the CYP21 protein, which is part of the heme coordinating system [27].

Physical interactions of CYP21A2

  • All eight chimeric CYP21 genes coupled with HLA-Bw47 in five unrelated patients had the CYP21A-CYP21B sequence transition within the same gene region (+1375 to +1993) [28].

Regulatory relationships of CYP21A2


Other interactions of CYP21A2

  • Tenascin-X: a novel extracellular matrix protein encoded by the human XB gene overlapping P450c21B [30].
  • Hybridization with specific oligonucleotide probes showed that in all 13 cases this remaining CYP21 gene carried an 8-base-pair deletion, typical of CYP21A, that prevents synthesis of a functional protein [31].
  • DESIGN: Molecular analysis was performed by direct sequencing of PCR amplified products of the CYP21A2 and CYP11B1 genes [32].
  • The remaining CRC's had deletions of C4 and/or CYP21 genes and were designated Bdel, Cdel and the like [33].
  • Crude sediment extracts, containing high concentrations of polycyclic aromatic hydrocarbons (PAHs) and moderate amounts of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) significantly stimulated expression of the CYP11B2 gene (up to 10-fold induction), and suppressed expression of 3betaHSD2 and CYP21 genes [34].

Analytical, diagnostic and therapeutic context of CYP21A2

  • This study used CYP21A2 genotyping (sequence/Southern blot analysis) to determine CAH carrier frequency in a middle European (Austrian) population [35].
  • Sequence analysis of the complete functional CYP21A2 gene revealed three, not yet described mutations that represent a common pseudogene sequence [36].
  • We performed simultaneous RFLP analyses of the CYP21 and C4 genes and determined the relative hybridization intensity of the genes using scanning densitometry of the X-ray films [37].
  • RESULTS: After careful titration, we found that earlier failure to detect the chimeric CYP21P/CYP21 gene could be caused by unequal concentrations of two independent alleles as the PCR template or by the lack of primers to amplify chimeric molecules [38].
  • Determination of deletion sizes in the MHC-linked complement C4 and steroid 21-hydroxylase genes by pulsed-field gel electrophoresis [39].


  1. Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes. Koppens, P.F., Hoogenboezem, T., Degenhart, H.J. Hum. Genet. (2002) [Pubmed]
  2. Carriership of a defective tenascin-X gene in steroid 21-hydroxylase deficiency patients: TNXB -TNXA hybrids in apparent large-scale gene conversions. Koppens, P.F., Hoogenboezem, T., Degenhart, H.J. Hum. Mol. Genet. (2002) [Pubmed]
  3. R339H and P453S: CYP21 mutations associated with nonclassic steroid 21-hydroxylase deficiency that are not apparent gene conversions. Helmberg, A., Tusie-Luna, M.T., Tabarelli, M., Kofler, R., White, P.C. Mol. Endocrinol. (1992) [Pubmed]
  4. Gene symbol: CYP21A2. Disease: adrenal hyperplasia, CYP21. Dain, L., Minutolo, C., Buzzalino, N., Belli, S., Oneto, A., Charreau, E., Alba, L. Hum. Genet. (2006) [Pubmed]
  5. Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes. Schaffer, F.M., Palermos, J., Zhu, Z.B., Barger, B.O., Cooper, M.D., Volanakis, J.E. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  6. Steroidogenic enzyme expression within the adrenal cortex during early human gestation. Goto, M., Brickwood, S., Wilson, D.I., Wood, P.J., Mason, J.I., Hanley, N.A. Endocr. Res. (2002) [Pubmed]
  7. Tenascin-X deficiency is associated with Ehlers-Danlos syndrome. Burch, G.H., Gong, Y., Liu, W., Dettman, R.W., Curry, C.J., Smith, L., Miller, W.L., Bristow, J. Nat. Genet. (1997) [Pubmed]
  8. A de novo pathological point mutation at the 21-hydroxylase locus: implications for gene conversion in the human genome. Collier, S., Tassabehji, M., Sinnott, P., Strachan, T. Nat. Genet. (1993) [Pubmed]
  9. Aldosterone synthesis in salt-wasting congenital adrenal hyperplasia with complete absence of adrenal 21-hydroxylase. Speiser, P.W., Agdere, L., Ueshiba, H., White, P.C., New, M.I. N. Engl. J. Med. (1991) [Pubmed]
  10. Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14,DR1. Speiser, P.W., New, M.I., White, P.C. N. Engl. J. Med. (1988) [Pubmed]
  11. Pro-453 to Ser mutation in CYP21 is associated with nonclassic steroid 21-hydroxylase deficiency. Owerbach, D., Sherman, L., Ballard, A.L., Azziz, R. Mol. Endocrinol. (1992) [Pubmed]
  12. Family studies of the steroid 21-hydroxylase and complement C4 genes define 11 haplotypes in classical congenital adrenal hyperplasia in The Netherlands. Koppens, P.F., Hoogenboezem, T., Halley, D.J., Barendse, C.A., Oostenbrink, A.J., Degenhart, H.J. Eur. J. Pediatr. (1992) [Pubmed]
  13. Difference in transcriptional activity of two homologous CYP21A genes. Chang, S.F., Chung, B.C. Mol. Endocrinol. (1995) [Pubmed]
  14. Identification of the recombination site within the steroid 21-hydroxylase gene (CYP21) of the HLA-B47,DR7 haplotype. Chu, X., Braun-Heimer, L., Rittner, C., Schneider, P.M. Exp. Clin. Immunogenet. (1992) [Pubmed]
  15. Naturally occurring mutants of human steroid 21-hydroxylase (P450c21) pinpoint residues important for enzyme activity and stability. Nikoshkov, A., Lajic, S., Vlamis-Gardikas, A., Tranebjaerg, L., Holst, M., Wedell, A., Luthman, H. J. Biol. Chem. (1998) [Pubmed]
  16. Substitutions in the CYP21A2 promoter explain the simple-virilizing form of 21-hydroxylase deficiency in patients harbouring a P30L mutation. Araujo, R.S., Billerbeck, A.E., Madureira, G., Mendonca, B.B., Bachega, T.A. Clin. Endocrinol. (Oxf) (2005) [Pubmed]
  17. Mutations in steroid 21-hydroxylase (CYP21). White, P.C., Tusie-Luna, M.T., New, M.I., Speiser, P.W. Hum. Mutat. (1994) [Pubmed]
  18. The suppression effect of DNA sequences within the C4A region on the transcription activity of human CYP21. Chang, S.F., Cheng, C.L. Endocr. Res. (1998) [Pubmed]
  19. Steroid 21-hydroxylase deficiency (congenital adrenal hyperplasia). New, M.I. Am. J. Med. (1995) [Pubmed]
  20. A novel cAMP-dependent regulatory region including a sequence like the cAMP-responsive element, far upstream of the human CYP21A2 gene. Watanabe, N., Kitazume, M., Fujisawa, J., Yoshida, M., Fujii-Kuriyama, Y. Eur. J. Biochem. (1993) [Pubmed]
  21. Expression profiling suggests a regulatory role of gallbladder in lipid homeostasis. Yuan, Z.B., Han, T.Q., Jiang, Z.Y., Fei, J., Zhang, Y., Qin, J., Tian, Z.J., Shang, J., Jiang, Z.H., Cai, X.X., Jiang, Y., Zhang, S.D. World J. Gastroenterol. (2005) [Pubmed]
  22. Cytochrome P450 oxidoreductase gene mutations and Antley-Bixler syndrome with abnormal genitalia and/or impaired steroidogenesis: molecular and clinical studies in 10 patients. 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. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  23. Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency: implication for the backdoor pathway to dihydrotestosterone. Homma, K., Hasegawa, T., Nagai, T., Adachi, M., Horikawa, R., Fujiwara, I., Tajima, T., Takeda, R., Fukami, M., Ogata, T. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  24. Clinical and biochemical description of a novel CYP21A2 gene mutation 962_963insA using a new 3D model for the P450c21 protein. Janner, M., Pandey, A.V., Mullis, P.E., Flück, C.E. Eur. J. Endocrinol. (2006) [Pubmed]
  25. Use of nonradioactive labeling to detect large gene rearrangements in 21-hydroxylase deficiency. Cukier, P., Bachega, T.A., Mendonça, B.B., Billerbeck, A.E. Revista do Hospital das Clínicas. (2004) [Pubmed]
  26. Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21-hydroxylase and complement C4 gene repeats in 21-hydroxylase deficiency haplotypes. Collier, S., Sinnott, P.J., Dyer, P.A., Price, D.A., Harris, R., Strachan, T. EMBO J. (1989) [Pubmed]
  27. Functional and structural consequences of a novel point mutation in the CYP21A2 gene causing congenital adrenal hyperplasia: potential relevance of helix C for P450 oxidoreductase-21-hydroxylase interaction. Riepe, F.G., Hiort, O., Grötzinger, J., Sippell, W.G., Krone, N., Holterhus, P.M. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  28. Two distinct areas of unequal crossingover within the steroid 21-hydroxylase genes produce absence of CYP21B. Donohoue, P.A., Jospe, N., Migeon, C.J., Van Dop, C. Genomics (1989) [Pubmed]
  29. A novel frameshift mutation (141delT) in exon 1 of the 21-hydroxylase gene (CYP21) in a patient with the salt wasting form of congenital adrenal hyperplasia. Mutation in brief no. 255. Online. Krone, N., Braun, A., Roscher, A.A., Schwarz, H.P. Hum. Mutat. (1999) [Pubmed]
  30. Tenascin-X: a novel extracellular matrix protein encoded by the human XB gene overlapping P450c21B. Bristow, J., Tee, M.K., Gitelman, S.E., Mellon, S.H., Miller, W.L. J. Cell Biol. (1993) [Pubmed]
  31. Characterization of frequent deletions causing steroid 21-hydroxylase deficiency. White, P.C., Vitek, A., Dupont, B., New, M.I. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  32. 21-Hydroxylase and 11beta-hydroxylase mutations in Romanian patients with classic congenital adrenal hyperplasia. Grigorescu Sido, A., Weber, M.M., Grigorescu Sido, P., Clausmeyer, S., Heinrich, U., Schulze, E. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  33. Relationship between protein complotypes and DNA variant haplotypes: complotype-RFLP constellations (CRC). Simon, S., Truedsson, L., Marcus-Bagley, D., Awdeh, Z., Eisenbarth, G.S., Brink, S.J., Yunis, E.J., Alper, C.A. Hum. Immunol. (1997) [Pubmed]
  34. Alteration of steroidogenesis in H295R cells by organic sediment contaminants and relationships to other endocrine disrupting effects. Bláha, L., Hilscherová, K., Mazurová, E., Hecker, M., Jones, P.D., Newsted, J.L., Bradley, P.W., Gracia, T., Duris, Z., Horká, I., Holoubek, I., Giesy, J.P. Environment international. (2006) [Pubmed]
  35. Carrier frequency of congenital adrenal hyperplasia (21-hydroxylase deficiency) in a middle European population. Baumgartner-Parzer, S.M., Nowotny, P., Heinze, G., Waldhäusl, W., Vierhapper, H. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  36. Three novel mutations in Japanese patients with 21-hydroxylase deficiency. Usui, T., Nishisho, K., Kaji, M., Ikuno, N., Yorifuji, T., Yasuda, T., Kuzuya, H., Shimatsu, A. Horm. Res. (2004) [Pubmed]
  37. CYP21B gene conversion and complete CYP21A gene deletion in congenital adrenal hyperplasia. Lobaccaro, J.M., Ghanem, N., Lefranc, G., Sultan, C. Ann. Genet. (1990) [Pubmed]
  38. Analysis of the chimeric CYP21P/CYP21 gene in steroid 21-hydroxylase deficiency. Lee, H.H., Chang, J.G., Tsai, C.H., Tsai, F.J., Chao, H.T., Chung, B. Clin. Chem. (2000) [Pubmed]
  39. Determination of deletion sizes in the MHC-linked complement C4 and steroid 21-hydroxylase genes by pulsed-field gel electrophoresis. Partanen, J., Kere, J., Wessberg, S., Koskimies, S. Genomics (1989) [Pubmed]
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