Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Adrenal Hyperplasia Type 3 or Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency
Homo sapiens
Disease Pathway
Created: 2013-08-19
Last Updated: 2023-07-30
Adrenal hyperplasia type 3, also called Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, is caused by a defect in the CYP21A2 gene which codes for Steroid 21-hydroxylase (21-hydroxylase). Steroid 21-hydroxylase catalyzes hydroxylation of 17-hydroxyprogesterone to 11-deoxycortisol in the glucocorticoid pathway from pregnenolone to cortisol. It also catalyzes hydroxylation of progesterone to 11-deoxycorticosterone (DOC) in the mineralocorticoid pathway on its way from pregnenolone to aldosterone. A defect in this enzyme results in accumulation of 17-Hydroxyprogesterone, progesterone and 17a-Hydroxypregnenolone, androstenedione, and testosterone; decreased levels of cortexolone, deoxycorticosterone, aldosterone and cortisol. Symptoms include salt-wasting crises in infancy due to the lack of aldosterone, like spitting, poor weight gain, vomiting, severe dehydration, and circulatory collapse. The high level of testosterone results in virilization and genital ambiguity of female infants.
References
Adrenal Hyperplasia Type 3 or Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency References
[Uniprot: P08686](http://www.uniprot.org/uniprot/P08686)
[eMedicine: Article 923876-diagnosis](http://emedicine.medscape.com/article/923876-diagnosis)
[Wikipedia: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency](http://en.wikipedia.org/wiki/Congenital_adrenal_hyperplasia_due_to_21-hydroxylase_deficiency)
[OMIM](http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=201910)
de-Araujo M, Sanches MR, Suzuki LA, Guerra G Jr, Farah SB, de-Mello MP: Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency. Braz J Med Biol Res. 1996 Jan;29(1):1-13.
Pubmed: 8731325
Araujo RS, Mendonca BB, Barbosa AS, Lin CJ, Marcondes JA, Billerbeck AE, Bachega TA: Microconversion between CYP21A2 and CYP21A1P promoter regions causes the nonclassical form of 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2007 Oct;92(10):4028-34. doi: 10.1210/jc.2006-2163. Epub 2007 Jul 31.
Pubmed: 17666484
Bachega TA, Billerbeck AE, Madureira G, Marcondes JA, Longui CA, Leite MV, Arnhold IJ, Mendonca BB: Molecular genotyping in Brazilian patients with the classical and nonclassical forms of 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1998 Dec;83(12):4416-9. doi: 10.1210/jcem.83.12.5350.
Pubmed: 9851787
BONGIOVANNI AM, ROOT AW: The adrenogenital syndrome. N Engl J Med. 1963 Jun 6;268:1283-9 contd. doi: 10.1056/NEJM196306062682308.
Pubmed: 13968788
Charmandari E, Hindmarsh PC, Johnston A, Brook CG: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: alterations in cortisol pharmacokinetics at puberty. J Clin Endocrinol Metab. 2001 Jun;86(6):2701-8. doi: 10.1210/jcem.86.6.7522.
Pubmed: 11397874
White PC, Bachega TA: Congenital adrenal hyperplasia due to 21 hydroxylase deficiency: from birth to adulthood. Semin Reprod Med. 2012 Oct;30(5):400-9. doi: 10.1055/s-0032-1324724. Epub 2012 Oct 8.
Pubmed: 23044877
https://www.omim.org/entry/201910
Steroidogenesis References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Norman, A.W, and Litwack, G. Hormones (2nd ed.) (1997) San Diego : Academic Press.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Vance, D.E., and Vance, J.E. Biochemistry of lipids, lipoproteins, and membranes (4th ed.) (2002) Amsterdam; Boston: Elsevier.
Miller WL: Molecular biology of steroid hormone synthesis. Endocr Rev. 1988 Aug;9(3):295-318. doi: 10.1210/edrv-9-3-295.
Pubmed: 3061784
HECHTER O, SOLOMON MM, ZAFFARONI A, PINCUS G: Transformation of cholesterol and acetate to adrenal cortical hormones. Arch Biochem Biophys. 1953 Sep;46(1):201-14. doi: 10.1016/0003-9861(53)90182-9.
Pubmed: 13092959
Luu-The V: Assessment of steroidogenesis and steroidogenic enzyme functions. J Steroid Biochem Mol Biol. 2013 Sep;137:176-82. doi: 10.1016/j.jsbmb.2013.05.017. Epub 2013 Jun 13.
Pubmed: 23770321
George FW, Russell DW, Wilson JD: Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha-reductase. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8044-7. doi: 10.1073/pnas.88.18.8044.
Pubmed: 1654556
Andersson S, Berman DM, Jenkins EP, Russell DW: Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism. Nature. 1991 Nov 14;354(6349):159-61. doi: 10.1038/354159a0.
Pubmed: 1944596
Emanuelsson I, Almokhtar M, Wikvall K, Gronbladh A, Nylander E, Svensson AL, Fex Svenningsen A, Norlin M: Expression and regulation of CYP17A1 and 3beta-hydroxysteroid dehydrogenase in cells of the nervous system: Potential effects of vitamin D on brain steroidogenesis. Neurochem Int. 2018 Feb;113:46-55. doi: 10.1016/j.neuint.2017.11.007. Epub 2017 Nov 21.
Pubmed: 29162485
Kimoto T, Asou H, Ohta Y, Mukai H, Chernogolov AA, Kawato S: Digital fluorescence imaging of elementary steps of neurosteroid synthesis in rat brain glial cells. J Pharm Biomed Anal. 1997 Jun;15(9-10):1231-40.
Pubmed: 9226548
Verschoor-Klootwyk AH, Verschoor L, Azhar S, Reaven GM: Role of exogenous cholesterol in regulation of adrenal steroidogenesis in the rat. J Biol Chem. 1982 Jul 10;257(13):7666-71.
Pubmed: 6282849
Qin KN, New MI, Cheng KC: Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3 alpha-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol. 1993 Dec;46(6):673-9.
Pubmed: 8274401
Khanna M, Qin KN, Wang RW, Cheng KC: Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases. J Biol Chem. 1995 Aug 25;270(34):20162-8. doi: 10.1074/jbc.270.34.20162.
Pubmed: 7650035
Khanna M, Qin KN, Cheng KC: Distribution of 3 alpha-hydroxysteroid dehydrogenase in rat brain and molecular cloning of multiple cDNAs encoding structurally related proteins in humans. J Steroid Biochem Mol Biol. 1995 Jun;53(1-6):41-6.
Pubmed: 7626489
Drury JE, Mindnich R, Penning TM: Characterization of disease-related 5beta-reductase (AKR1D1) mutations reveals their potential to cause bile acid deficiency. J Biol Chem. 2010 Aug 6;285(32):24529-37. doi: 10.1074/jbc.M110.127779. Epub 2010 Jun 3.
Pubmed: 20522910
Di Costanzo L, Drury JE, Penning TM, Christianson DW: Crystal structure of human liver Delta4-3-ketosteroid 5beta-reductase (AKR1D1) and implications for substrate binding and catalysis. J Biol Chem. 2008 Jun 13;283(24):16830-9. doi: 10.1074/jbc.M801778200. Epub 2008 Apr 11.
Pubmed: 18407998
Di Costanzo L, Drury JE, Christianson DW, Penning TM: Structure and catalytic mechanism of human steroid 5beta-reductase (AKR1D1). Mol Cell Endocrinol. 2009 Mar 25;301(1-2):191-8. doi: 10.1016/j.mce.2008.09.013. Epub 2008 Sep 19.
Pubmed: 18848863
Pascoe L, Curnow KM, Slutsker L, Rosler A, White PC: Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4996-5000. doi: 10.1073/pnas.89.11.4996.
Pubmed: 1594605
Mitsuuchi Y, Kawamoto T, Naiki Y, Miyahara K, Toda K, Kuribayashi I, Orii T, Yasuda K, Miura K, Nakao K, et al.: Congenitally defective aldosterone biosynthesis in humans: the involvement of point mutations of the P-450C18 gene (CYP11B2) in CMO II deficient patients. Biochem Biophys Res Commun. 1992 Jan 31;182(2):974-9. doi: 10.1016/0006-291x(92)91827-d.
Pubmed: 1346492
Mitsuuchi Y, Kawamoto T, Miyahara K, Ulick S, Morton DH, Naiki Y, Kuribayashi I, Toda K, Hara T, Orii T, et al.: Congenitally defective aldosterone biosynthesis in humans: inactivation of the P-450C18 gene (CYP11B2) due to nucleotide deletion in CMO I deficient patients. Biochem Biophys Res Commun. 1993 Feb 15;190(3):864-9. doi: 10.1006/bbrc.1993.1128.
Pubmed: 8439335
Naiki Y, Kawamoto T, Mitsuuchi Y, Miyahara K, Toda K, Orii T, Imura H, Shizuta Y: A nonsense mutation (TGG [Trp116]-->TAG [Stop]) in CYP11B1 causes steroid 11 beta-hydroxylase deficiency. J Clin Endocrinol Metab. 1993 Dec;77(6):1677-82. doi: 10.1210/jcem.77.6.7903314.
Pubmed: 7903314
White PC, Dupont J, New MI, Leiberman E, Hochberg Z, Rosler A: A mutation in CYP11B1 (Arg-448----His) associated with steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin. J Clin Invest. 1991 May;87(5):1664-7. doi: 10.1172/JCI115182.
Pubmed: 2022736
Joehrer K, Geley S, Strasser-Wozak EM, Azziz R, Wollmann HA, Schmitt K, Kofler R, White PC: CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Hum Mol Genet. 1997 Oct;6(11):1829-34. doi: 10.1093/hmg/6.11.1829.
Pubmed: 9302260
Tannin GM, Agarwal AK, Monder C, New MI, White PC: The human gene for 11 beta-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization. J Biol Chem. 1991 Sep 5;266(25):16653-8.
Pubmed: 1885595
Draper N, Echwald SM, Lavery GG, Walker EA, Fraser R, Davies E, Sorensen TI, Astrup A, Adamski J, Hewison M, Connell JM, Pedersen O, Stewart PM: Association studies between microsatellite markers within the gene encoding human 11beta-hydroxysteroid dehydrogenase type 1 and body mass index, waist to hip ratio, and glucocorticoid metabolism. J Clin Endocrinol Metab. 2002 Nov;87(11):4984-90. doi: 10.1210/jc.2001-011375.
Pubmed: 12414862
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Higashi Y, Yoshioka H, Yamane M, Gotoh O, Fujii-Kuriyama Y: Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene. Proc Natl Acad Sci U S A. 1986 May;83(9):2841-5. doi: 10.1073/pnas.83.9.2841.
Pubmed: 3486422
White PC, New MI, Dupont B: Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5111-5. doi: 10.1073/pnas.83.14.5111.
Pubmed: 3487786
Rodrigues NR, Dunham I, Yu CY, Carroll MC, Porter RR, Campbell RD: Molecular characterization of the HLA-linked steroid 21-hydroxylase B gene from an individual with congenital adrenal hyperplasia. EMBO J. 1987 Jun;6(6):1653-61.
Pubmed: 3038528
Chung BC, Picado-Leonard J, Haniu M, Bienkowski M, Hall PF, Shively JE, Miller WL: Cytochrome P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proc Natl Acad Sci U S A. 1987 Jan;84(2):407-11. doi: 10.1073/pnas.84.2.407.
Pubmed: 3025870
Picado-Leonard J, Miller WL: Cloning and sequence of the human gene for P450c17 (steroid 17 alpha-hydroxylase/17,20 lyase): similarity with the gene for P450c21. DNA. 1987 Oct;6(5):439-48. doi: 10.1089/dna.1987.6.439.
Pubmed: 3500022
Bradshaw KD, Waterman MR, Couch RT, Simpson ER, Zuber MX: Characterization of complementary deoxyribonucleic acid for human adrenocortical 17 alpha-hydroxylase: a probe for analysis of 17 alpha-hydroxylase deficiency. Mol Endocrinol. 1987 May;1(5):348-54. doi: 10.1210/mend-1-5-348.
Pubmed: 3274893
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings