ID CP21A_HUMAN Reviewed; 495 AA. AC P08686; A2BHY6; P04033; Q01204; Q08AG8; Q16749; Q16806; Q16874; Q5ST44; AC Q96NU8; DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot. DT 24-JAN-2024, sequence version 2. DT 27-MAR-2024, entry version 242. DE RecName: Full=Steroid 21-hydroxylase {ECO:0000303|PubMed:25855791}; DE EC=1.14.14.16 {ECO:0000269|PubMed:16984992, ECO:0000269|PubMed:22014889, ECO:0000269|PubMed:25855791, ECO:0000269|PubMed:27721825}; DE AltName: Full=21-OHase; DE AltName: Full=Cytochrome P-450c21; DE AltName: Full=Cytochrome P450 21; DE AltName: Full=Cytochrome P450 XXI; DE AltName: Full=Cytochrome P450-C21; DE AltName: Full=Cytochrome P450-C21B; GN Name=CYP21A2; Synonyms=CYP21, CYP21B; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE CYP21A2*1A), AND VARIANTS LEU-6 RP DEL; LYS-103 AND ASN-494. RX PubMed=3486422; DOI=10.1073/pnas.83.9.2841; RA Higashi Y., Yoshioka H., Yamane M., Gotoh O., Fujii-Kuriyama Y.; RT "Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly RT arranged in human chromosome: a pseudogene and a genuine gene."; RL Proc. Natl. Acad. Sci. U.S.A. 83:2841-2845(1986). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ALLELE CYP21A2*1B) (ISOFORM 1), RP AND VARIANTS LEU-6 DEL AND ASN-494. RX PubMed=3487786; DOI=10.1073/pnas.83.14.5111; RA White P.C., New M.I., Dupont B.; RT "Structure of human steroid 21-hydroxylase genes."; RL Proc. Natl. Acad. Sci. U.S.A. 83:5111-5115(1986). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT AH3 THR-269, VARIANTS LYS-103 RP AND ASN-494, AND INVOLVEMENT IN AH3. RX PubMed=3038528; DOI=10.1002/j.1460-2075.1987.tb02414.x; RA Rodrigues N.R., Dunham I., Yu C.Y., Carroll M.C., Porter R.R., RA Campbell R.D.; RT "Molecular characterization of the HLA-linked steroid 21-hydroxylase B gene RT from an individual with congenital adrenal hyperplasia."; RL EMBO J. 6:1653-1661(1987). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT AH3 LEU-282. RX PubMed=3267225; DOI=10.1172/jci113562; RA Globerman H., Amor M., Parker K.L., New M.I., White P.C.; RT "Nonsense mutation causing steroid 21-hydroxylase deficiency."; RL J. Clin. Invest. 82:139-144(1988). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS AH3 HIS-340 AND SER-454. RC TISSUE=Peripheral blood; RX PubMed=1406709; DOI=10.1210/mend.6.8.1406709; RA Helmberg A., Tusie-Luna M.-T., Tabarelli M., Kofler R., White P.C.; RT "R339H and P453S: CYP21 mutations associated with nonclassic steroid 21- RT hydroxylase deficiency that are not apparent gene conversions."; RL Mol. Endocrinol. 6:1318-1322(1992). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-6 DEL; LYS-103 AND RP ASN-494. RX PubMed=19505723; DOI=10.1016/j.molimm.2009.04.033; RA Blasko B., Banlaki Z., Gyapay G., Pozsonyi E., Sasvari-Szekely M., RA Rajczy K., Fust G., Szilagyi A.; RT "Linkage analysis of the C4A/C4B copy number variation and polymorphisms of RT the adjacent steroid 21-hydroxylase gene in a healthy population."; RL Mol. Immunol. 46:2623-2629(2009). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=23241443; DOI=10.1093/gbe/evs121; RA Banlaki Z., Szabo J.A., Szilagyi A., Patocs A., Prohaszka Z., Fust G., RA Doleschall M.; RT "Intraspecific evolution of human RCCX copy number variation traced by RT haplotypes of the CYP21A2 gene."; RL Genome Biol. Evol. 5:98-112(2013). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=24312389; DOI=10.1371/journal.pone.0081977; RA Szabo J.A., Szilagyi A., Doleschall Z., Patocs A., Farkas H., Prohaszka Z., RA Racz K., Fuest G., Doleschall M.; RT "Both positive and negative selection pressures contribute to the RT polymorphism pattern of the duplicated human CYP21A2 gene."; RL PLoS ONE 8:e81977-e81977(2013). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=28401898; DOI=10.1038/ejhg.2017.38; RA Doleschall M., Luczay A., Koncz K., Hadzsiev K., Erhardt E., Szilagyi A., RA Doleschall Z., Nemeth K., Toeroek D., Prohaszka Z., Gereben B., Fekete G., RA Glaz E., Igaz P., Korbonits M., Toth M., Racz K., Patocs A.; RT "A unique haplotype of RCCX copy number variation: from the clinics of RT congenital adrenal hyperplasia to evolutionary genetics."; RL Eur. J. Hum. Genet. 25:702-710(2017). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ALLELE CYP21A2*6) (ISOFORMS 1 AND RP 2). RC TISSUE=Adrenal gland; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14656967; DOI=10.1101/gr.1736803; RA Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S., Campbell R.D., RA Hood L.; RT "Analysis of the gene-dense major histocompatibility complex class III RT region and its comparison to mouse."; RL Genome Res. 13:2621-2636(2003). RN [12] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [13] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [14] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT LYS-103. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [15] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 110-186, AND VARIANT AH3 ASN-173. RX PubMed=8485582; DOI=10.1038/ng0393-260; RA Collier S., Tassabehji M., Sinnott P., Strachan T.; RT "A de novo pathological point mutation at the 21-hydroxylase locus: RT implications for gene conversion in the human genome."; RL Nat. Genet. 3:260-265(1993). RN [16] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 150-183, AND VARIANT AH3 ASN-173. RX PubMed=3871526; DOI=10.1073/pnas.82.2.521; RA Carroll M.C., Campbell R.D., Porter R.R.; RT "Mapping of steroid 21-hydroxylase genes adjacent to complement component RT C4 genes in HLA, the major histocompatibility complex in man."; RL Proc. Natl. Acad. Sci. U.S.A. 82:521-525(1985). RN [17] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 150-183, AND VARIANT AH3 ASN-173. RX PubMed=3257825; DOI=10.1073/pnas.85.5.1600; RA Amor M., Parker K.L., Globerman H., New M.I., White P.C.; RT "Mutation in the CYP21B gene (Ile-172-->Asn) causes steroid 21-hydroxylase RT deficiency."; RL Proc. Natl. Acad. Sci. U.S.A. 85:1600-1604(1988). RN [18] RP NUCLEOTIDE SEQUENCE [MRNA] OF 266-495 (ISOFORM 1), VARIANT AH3 LEU-282, AND RP VARIANT ASN-494. RX PubMed=3497399; DOI=10.1073/pnas.84.16.5858; RA Matteson K.J., Phillips J.A. III, Miller W.L., Chung B.C., Orlando P.J., RA Frisch H., Ferrandez A., Burr I.M.; RT "P450XXI (steroid 21-hydroxylase) gene deletions are not found in family RT studies of congenital adrenal hyperplasia."; RL Proc. Natl. Acad. Sci. U.S.A. 84:5858-5862(1987). RN [19] RP FUNCTION. RX PubMed=10602386; DOI=10.1038/sj.gt.3301018; RA Tajima T., Okada T., Ma X.M., Ramsey W., Bornstein S., Aguilera G.; RT "Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of RT human cytochromeP450 21-hydroxylase into the adrenal gland of21- RT hydroxylase-deficient mice."; RL Gene Ther. 6:1898-1903(1999). RN [20] {ECO:0007744|PDB:4Y8W} RP X-RAY CRYSTALLOGRAPHY (2.64 ANGSTROMS) OF 30-495 IN COMPLEX WITH HEME AND RP PROGESTERONE, FUNCTION, COFACTOR, CATALYTIC ACTIVITY, AND RP BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=25855791; DOI=10.1074/jbc.m115.646307; RA Pallan P.S., Wang C., Lei L., Yoshimoto F.K., Auchus R.J., Waterman M.R., RA Guengerich F.P., Egli M.; RT "Human Cytochrome P450 21A2, the major steroid 21-hydroxylase: structure of RT the enzyme-progesterone substrate complex and rate-limiting c-h bond RT cleavage."; RL J. Biol. Chem. 290:13128-13143(2015). RN [21] RP CHARACTERIZATION OF VARIANT AH3 LEU-282, AND MUTAGENESIS OF SER-269; RP VAL-282 AND CYS-429. RX PubMed=1864962; DOI=10.1172/jci115334; RA Wu D.-A., Chung B.-C.; RT "Mutations of P450c21 (steroid 21-hydroxylase) at Cys428, Val281, and RT Ser268 result in complete, partial, or no loss of enzymatic activity, RT respectively."; RL J. Clin. Invest. 88:519-523(1991). RN [22] RP POLYMORPHISM. RX PubMed=8081391; DOI=10.1002/humu.1380030408; RA White P.C., Tusie-Luna M.-T., New M.I., Speiser P.W.; RT "Mutations in steroid 21-hydroxylase (CYP21)."; RL Hum. Mutat. 3:373-378(1994). RN [23] RP VARIANTS AH3 LEU-212 AND LEU-282. RX PubMed=3260007; DOI=10.1056/nejm198807073190104; RA Speiser P.W., New M.I., White P.C.; RT "Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency RT associated with HLA-B14,DR1."; RL N. Engl. J. Med. 319:19-23(1988). RN [24] RP VARIANTS AH3 ASN-173 AND TRP-357. RX PubMed=2303461; DOI=10.1016/s0021-9258(19)39804-7; RA Chiou S.-H., Hu M.-C., Chung B.-C.; RT "A missense mutation at Ile172-->Asn or Arg356-->Trp causes steroid 21- RT hydroxylase deficiency."; RL J. Biol. Chem. 265:3549-3552(1990). RN [25] RP VARIANT AH3 ASN-173. RX PubMed=1937474; DOI=10.1007/bf00201731; RA Partanen J., Campbell R.D.; RT "Substitution of Ile-172 to Asn in the steroid 21-hydroxylase B (P450c21B) RT gene in a Finnish patient with the simple virilizing form of congenital RT adrenal hyperplasia."; RL Hum. Genet. 87:716-720(1991). RN [26] RP VARIANT AH3 LEU-31, AND VARIANT THR-269. RX PubMed=2072928; DOI=10.1210/mend-5-5-685; RA Tusie-Luna M.T., Speiser P.W., Dumic M., New M.I., White P.C.; RT "A mutation (Pro-30 to Leu) in CYP21 represents a potential nonclassic RT steroid 21-hydroxylase deficiency allele."; RL Mol. Endocrinol. 5:685-692(1991). RN [27] RP VARIANTS AH3 LEU-31; ASN-173; ASN-237; GLU-238; LYS-240; LEU-282 AND RP TRP-357. RX PubMed=1644925; DOI=10.1172/jci115897; RA Speiser P.W., Dupont J., Zhu D., Serrat J., Buegeleisen M., RA Tusie-Luna M.-T., Lesser M., New M.I., White P.C.; RT "Disease expression and molecular genotype in congenital adrenal RT hyperplasia due to 21-hydroxylase deficiency."; RL J. Clin. Invest. 90:584-595(1992). RN [28] RP VARIANT AH3 SER-454. RX PubMed=1406699; DOI=10.1210/mend.6.8.1406699; RA Owerbach D., Sherman L., Ballard A.L., Azziz R.; RT "Pro-453 to Ser mutation in CYP21 is associated with nonclassic steroid 21- RT hydroxylase deficiency."; RL Mol. Endocrinol. 6:1211-1215(1992). RN [29] RP VARIANTS AH3 LEU-106; SER-292 AND SER-454. RX PubMed=1496017; DOI=10.1073/pnas.89.15.7232; RA Wedell A., Ritzen E.M., Haglund-Stengler B., Luthman H.; RT "Steroid 21-hydroxylase deficiency: three additional mutated alleles and RT establishment of phenotype-genotype relationships of common mutations."; RL Proc. Natl. Acad. Sci. U.S.A. 89:7232-7236(1992). RN [30] RP VARIANT AH3 PRO-484. RX PubMed=8478006; DOI=10.1007/bf00218263; RA Wedell A., Luthman H.; RT "Steroid 21-hydroxylase (P450c21): a new allele and spread of mutations RT through the pseudogene."; RL Hum. Genet. 91:236-240(1993). RN [31] RP VARIANTS AH3 ASN-173; ASN-237; LEU-282 AND PRO-484. RX PubMed=7749410; DOI=10.1002/humu.1380050205; RA Barbat B., Bogyo A., Raux-Demay M.-C., Kuttenn F., Boue J., Simon-Bouy B., RA Serre J.-L., Boue A., Mornet E.; RT "Screening of CYP21 gene mutations in 129 French patients affected by RT steroid 21-hydroxylase deficiency."; RL Hum. Mutat. 5:126-130(1995). RN [32] RP VARIANT AH3 ASP-381. RX PubMed=9067760; RX DOI=10.1002/(sici)1098-1004(1997)9:2<181::aid-humu12>3.0.co;2-z; RA Kirby-Keyser L., Porter C.C., Donohoue P.A.; RT "E380D: a novel point mutation of CYP21 in an HLA-homozygous patient with RT salt-losing congenital adrenal hyperplasia due to 21-hydroxylase RT deficiency."; RL Hum. Mutat. 9:181-182(1997). RN [33] RP VARIANTS AH3 PRO-357 AND GLN-357. RX PubMed=9187661; DOI=10.1007/s004390050436; RA Lajic S., Levo A., Nikoshkov A., Lundberg Y., Partanen J., Wedell A.; RT "A cluster of missense mutations at Arg356 of human steroid 21-hydroxylase RT may impair redox partner interaction."; RL Hum. Genet. 99:704-709(1997). RN [34] RP VARIANTS AH3 LEU-106 AND SER-454. RX PubMed=8989258; DOI=10.1210/jcem.82.1.3678; RA Nikoshkov A., Lajic S., Holst M., Wedell A., Luthman H.; RT "Synergistic effect of partially inactivating mutations in steroid 21- RT hydroxylase deficiency."; RL J. Clin. Endocrinol. Metab. 82:194-199(1997). RN [35] RP VARIANTS ARG-99; LYS-103; GLU-184 AND ASN-494. RX PubMed=9580109; DOI=10.1007/s004390050672; RA Ordonez-Sanchez M.L., Ramirez-Jimenez S., Lopez-Gutierrez A.U., Riba L., RA Gamboa-Cardiel S., Cerrillo-Hinojosa M., Altamirano-Bustamante N., RA Calzada-Leon R., Robles-Valdes C., Mendoza-Morfin F., Tusie-Luna M.T.; RT "Molecular genetic analysis of patients carrying steroid 21-hydroxylase RT deficiency in the Mexican population: identification of possible new RT mutations and high prevalence of apparent germ-line mutations."; RL Hum. Genet. 102:170-177(1998). RN [36] RP VARIANTS AH3 GLU-197 DEL; SER-292 AND PRO-484. RX PubMed=9497336; DOI=10.1074/jbc.273.11.6163; RA Nikoshkov A., Lajic S., Vlamis-Gardikas A., Tranebjaerg L., Holst M., RA Wedell A., Luthman H.; RT "Naturally occurring mutants of human steroid 21-hydroxylase (P450c21) RT pinpoint residues important for enzyme activity and stability."; RL J. Biol. Chem. 273:6163-6165(1998). RN [37] RP VARIANT AH3 GLN-31, CHARACTERIZATION OF VARIANT AH3 GLN-31, SUBCELLULAR RP LOCATION, TOPOLOGY, AND DOMAIN. RX PubMed=10198222; DOI=10.1006/bbrc.1999.0482; RA Lajic S., Nikoshkov A., Holst M., Wedell A.; RT "Effects of missense mutations and deletions on membrane anchoring and RT enzyme function of human steroid 21-hydroxylase (P450c21)."; RL Biochem. Biophys. Res. Commun. 257:384-390(1999). RN [38] RP VARIANTS AH3 LEU-31; VAL-91; ASN-173; ALA-179; LEU-282; CYS-292; HIS-355; RP TRP-357 AND SER-454. RX PubMed=10364682; DOI=10.1159/000022866; RA Lobato M.N., Ordonez-Sanchez M.L., Tusie-Luna M.T., Meseguer A.; RT "Mutation analysis in patients with congenital adrenal hyperplasia in the RT Spanish population: identification of putative novel steroid 21-hydroxylase RT deficiency alleles associated with the classic form of the disease."; RL Hum. Hered. 49:169-175(1999). RN [39] RP VARIANTS AH3 TYR-170; LEU-282 AND GLN-357. RX PubMed=10094562; RX DOI=10.1002/(sici)1098-1004(1999)13:2<172::aid-humu17>3.0.co;2-n; RA Witchel S.F., Smith R., Suda-Hartman M.; RT "Identification of CYP21 mutations, one novel, by single strand RT conformational polymorphism (SSCP) analysis."; RL Hum. Mutat. 13:172-172(1999). RN [40] RP VARIANTS AH3 LEU-31; GLU-65; ASN-173; ASN-237; LEU-282; SER-292; TRP-357 RP AND VAL-363. RX PubMed=10408778; RX DOI=10.1002/(sici)1098-1004(1999)13:6<482::aid-humu8>3.0.co;2-0; RA Ohlsson G., Mueller J., Skakkebaek N.E., Schwartz M.; RT "Steroid 21-hydroxylase deficiency: mutational spectrum in Denmark, three RT novel mutations, and in vitro expression analysis."; RL Hum. Mutat. 13:482-486(1999). RN [41] RP VARIANTS AH3 LEU-31; ASN-173; ASN-237; GLU-238; LYS-240; LEU-282 AND RP TRP-357. RX PubMed=10408786; RX DOI=10.1002/(sici)1098-1004(1999)13:6<505::aid-humu16>3.0.co;2-0; RA Kapelari K., Ghanaati Z., Wollmann H., Ventz M., Ranke M.B., Kofler R., RA Peters H.; RT "A rapid screening for steroid 21-hydroxylase mutations in patients with RT congenital adrenal hyperplasia."; RL Hum. Mutat. 13:505-505(1999). RN [42] RP VARIANTS AH3 LEU-282; TRP-357 AND SER-425. RX PubMed=10443693; DOI=10.1210/jcem.84.8.5937; RA Billerbeck A.E.C., Bachega T.A.S.S., Frazatto E.T., Nishi M.Y., RA Goldberg A.C., Marin M.L.C., Madureira G., Monte O., Arnhold I.J.P., RA Mendonca B.B.; RT "A novel missense mutation, GLY424SER, in Brazilian patients with 21- RT hydroxylase deficiency."; RL J. Clin. Endocrinol. Metab. 84:2870-2872(1999). RN [43] RP VARIANTS AH3 LEU-31; ASN-173; LEU-282 AND TRP-357, AND VARIANT THR-269. RX PubMed=10496074; DOI=10.1007/s100380050167; RA Asanuma A., Ohura T., Ogawa E., Sato S., Igarashi Y., Matsubara Y., RA Iinuma K.; RT "Molecular analysis of Japanese patients with steroid 21-hydroxylase RT deficiency."; RL J. Hum. Genet. 44:312-317(1999). RN [44] RP VARIANTS AH3 ASN-173 AND TRP-357. RX PubMed=10051010; RA Lako M., Ramsden S., Campbell R.D., Strachan T.; RT "Mutation screening in British 21-hydroxylase deficiency families and RT development of novel microsatellite based approaches to prenatal RT diagnosis."; RL J. Med. Genet. 36:119-124(1999). RN [45] RP VARIANTS AH3 LEU-282 AND SER-454, AND VARIANT THR-269. RX PubMed=10391209; DOI=10.1038/10290; RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RT "Characterization of single-nucleotide polymorphisms in coding regions of RT human genes."; RL Nat. Genet. 22:231-238(1999). RN [46] RP ERRATUM OF PUBMED:10391209. RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RL Nat. Genet. 23:373-373(1999). RN [47] RP VARIANTS AH3 LEU-31; ASN-173; LEU-282; GLY-282; PHE-301; CYS-355; TRP-357 RP AND SER-454. RX PubMed=10720040; DOI=10.1210/jcem.85.3.6441; RA Krone N., Braun A., Roscher A.A., Knorr D., Schwarz H.P.; RT "Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive RT genotyping in 155 unrelated, well defined patients from southern Germany."; RL J. Clin. Endocrinol. Metab. 85:1059-1065(2000). RN [48] RP VARIANTS AH3 LEU-31; ASN-173; PRO-262; TRP-357 AND PRO-484. RX PubMed=11598371; DOI=10.1159/000049992; RA Loke K.Y., Lee Y.S., Lee W.W.R., Poh L.K.S.; RT "Molecular analysis of CYP-21 mutations for congenital adrenal hyperplasia RT in Singapore."; RL Horm. Res. 55:179-184(2001). RN [49] RP VARIANTS AH3 LEU-31; ASN-173; LEU-282; MET-318; TRP-357; CYS-436 AND RP SER-454. RX PubMed=11232002; DOI=10.1210/jcem.86.1.7131; RA Deneux C., Tardy V., Dib A., Mornet E., Billaud L., Charron D., Morel Y., RA Kuttenn F.; RT "Phenotype-genotype correlation in 56 women with nonclassical congenital RT adrenal hyperplasia due to 21-hydroxylase deficiency."; RL J. Clin. Endocrinol. Metab. 86:207-213(2001). RN [50] RP VARIANTS AH3 LEU-31; ASN-173; LEU-282; SER-292; TRP-357; SER-425; HIS-427; RP SER-454 AND PRO-484, AND CHARACTERIZATION OF VARIANT AH3 HIS-427. RX PubMed=11600539; DOI=10.1210/jcem.86.10.7898; RA Baumgartner-Parzer S.M., Schulze E., Waldhaeusl W., Pauschenwein S., RA Rondot S., Nowotny P., Meyer K., Frisch H., Waldhauser F., Vierhapper H.; RT "Mutational spectrum of the steroid 21-hydroxylase gene in Austria: RT identification of a novel missense mutation."; RL J. Clin. Endocrinol. Metab. 86:4771-4775(2001). RN [51] RP VARIANT AH3 TRP-364. RX PubMed=11746135; DOI=10.1002/pd.167; RA Levo A., Partanen J.; RT "Novel mutations in the human CYP21 gene."; RL Prenat. Diagn. 21:885-889(2001). RN [52] RP VARIANTS AH3 LEU-31; ASN-173; LEU-282; LEU-284; TRP-357 AND SER-454. RX PubMed=12222711; DOI=10.1080/080352502760148595; RA Ezquieta B., Cueva E., Varela J., Oliver A., Fernandez J., Jariego C.; RT "Non-classical 21-hydroxylase deficiency in children: association of RT adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone with the risk RT of compound heterozygosity with severe mutations."; RL Acta Paediatr. 91:892-898(2002). RN [53] RP VARIANTS HYPERANDROGENISM MET-305; SER-376 AND SER-454, AND RP CHARACTERIZATION OF VARIANTS HYPERANDROGENISM MET-305; SER-376 AND SER-454. RX PubMed=12050257; DOI=10.1210/jcem.87.6.8525; RA Lajic S., Clauin S., Robins T., Vexiau P., Blanche H., RA Bellanne-Chantelot C., Wedell A.; RT "Novel mutations in CYP21 detected in individuals with hyperandrogenism."; RL J. Clin. Endocrinol. Metab. 87:2824-2829(2002). RN [54] RP VARIANTS AH3 CYS-409 AND SER-425. RX PubMed=12213891; DOI=10.1210/jc.2001-011939; RA Billerbeck A.E.C., Mendonca B.B., Pinto E.M., Madureira G., Arnhold I.J.P., RA Bachega T.A.S.S.; RT "Three novel mutations in CYP21 gene in Brazilian patients with the RT classical form of 21-hydroxylase deficiency due to a founder effect."; RL J. Clin. Endocrinol. Metab. 87:4314-4317(2002). RN [55] RP VARIANTS AH3 THR-16; LEU-31; ASN-173; LEU-282 AND SER-454. RX PubMed=12887291; DOI=10.1530/eje.0.1490137; RA Dolzan V., Stopar-Obreza M., Zerjav-Tansek M., Breskvar K., Krzisnik C., RA Battelino T.; RT "Mutational spectrum of congenital adrenal hyperplasia in Slovenian RT patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene RT conversion associated with a severe form of the disease."; RL Eur. J. Endocrinol. 149:137-144(2003). RN [56] RP VARIANTS AH3 LEU-31; LEU-63; ASN-173; LEU-282; PRO-342; TRP-357; SER-454 RP AND PRO-484. RX PubMed=12788866; DOI=10.1210/jc.2002-021433; RA Pinto G., Tardy V., Trivin C., Thalassinos C., Lortat-Jacob S., RA Nihoul-Fekete C., Morel Y., Brauner R.; RT "Follow-up of 68 children with congenital adrenal hyperplasia due to 21- RT hydroxylase deficiency: relevance of genotype for management."; RL J. Clin. Endocrinol. Metab. 88:2624-2633(2003). RN [57] RP VARIANTS AH3 ASN-173; LEU-282; ARG-292; TYR-302; TRP-357 AND GLN-484. RX PubMed=12915679; DOI=10.1210/jc.2002-021681; RA Stikkelbroeck N.M., Hoefsloot L.H., de Wijs I.J., Otten B.J., Hermus A.R., RA Sistermans E.A.; RT "CYP21 gene mutation analysis in 198 patients with 21-hydroxylase RT deficiency in The Netherlands: six novel mutations and a specific cluster RT of four mutations."; RL J. Clin. Endocrinol. Metab. 88:3852-3859(2003). RN [58] RP VARIANTS AH3 ASN-173; TRP-357 AND TRP-484. RX PubMed=14715874; DOI=10.1210/jc.2003-031056; RA Kharrat M., Tardy V., M'Rad R., Maazoul F., Jemaa L.B., Refai M., Morel Y., RA Chaabouni H.; RT "Molecular genetic analysis of Tunisian patients with a classic form of 21- RT hydroxylase deficiency: identification of four novel mutations and high RT prevalence of Q318X mutation."; RL J. Clin. Endocrinol. Metab. 89:368-374(2004). RN [59] RP VARIANT AH3 HIS-125. RX PubMed=14676460; DOI=10.1159/000075587; RA Usui T., Nishisho K., Kaji M., Ikuno N., Yorifuji T., Yasuda T., Kuzuya H., RA Shimatsu A.; RT "Three novel mutations in Japanese patients with 21-hydroxylase RT deficiency."; RL Horm. Res. 61:126-132(2004). RN [60] RP VARIANTS AH3 THR-16; LEU-31; LEU-282 AND SER-483, AND CHARACTERIZATION OF RP VARIANTS AH3 THR-16 AND SER-483. RX PubMed=15126570; DOI=10.1210/jc.2003-031630; RA Barbaro M., Lajic S., Baldazzi L., Balsamo A., Pirazzoli P., Cicognani A., RA Wedell A., Cacciari E.; RT "Functional analysis of two recurrent amino acid substitutions in the CYP21 RT gene from Italian patients with congenital adrenal hyperplasia."; RL J. Clin. Endocrinol. Metab. 89:2402-2407(2004). RN [61] RP VARIANTS AH3 LEU-31; ASN-173; ASN-237; GLU-238; LYS-240; LEU-282; SER-292; RP GLN-357; TRP-357; TYR-366; SER-454; LEU-480 AND PRO-484. RX PubMed=15110320; DOI=10.1016/j.ymgme.2004.02.006; RA Zeng X., Witchel S.F., Dobrowolski S.F., Moulder P.V., Jarvik J.W., RA Telmer C.A.; RT "Detection and assignment of CYP21 mutations using peptide mass signature RT genotyping."; RL Mol. Genet. Metab. 82:38-47(2004). RN [62] RP VARIANTS AH3 LEU-31; ASN-173 AND TRP-357. RX PubMed=16046588; DOI=10.1210/jc.2005-0379; RA Grigorescu Sido A., Weber M.M., Grigorescu Sido P., Clausmeyer S., RA Heinrich U., Schulze E.; RT "21-Hydroxylase and 11beta-hydroxylase mutations in Romanian patients with RT classic congenital adrenal hyperplasia."; RL J. Clin. Endocrinol. Metab. 90:5769-5773(2005). RN [63] RP VARIANTS AH3 ARG-170; ARG-179; ARG-303 AND CYS-427, CHARACTERIZATION OF RP VARIANTS AH3 ARG-170; ARG-179; ARG-303; CYS-427 AND HIS-427, FUNCTION, AND RP CATALYTIC ACTIVITY. RX PubMed=16984992; DOI=10.1210/jc.2006-0777; RA Grischuk Y., Rubtsov P., Riepe F.G., Groetzinger J., Beljelarskaia S., RA Prassolov V., Kalintchenko N., Semitcheva T., Peterkova V., Tiulpakov A., RA Sippell W.G., Krone N.; RT "Four novel missense mutations in the CYP21A2 gene detected in Russian RT patients suffering from the classical form of congenital adrenal RT hyperplasia: identification, functional characterization, and structural RT analysis."; RL J. Clin. Endocrinol. Metab. 91:4976-4980(2006). RN [64] RP VARIANTS AH3 LEU-31; LEU-63; ASN-173; TRP-357 AND SER-454, AND RP CHARACTERIZATION OF VARIANTS AH3 LEU-63 AND SER-454. RX PubMed=18319307; DOI=10.1210/jc.2007-2701; RA Menassa R., Tardy V., Despert F., Bouvattier-Morel C., Brossier J.P., RA Cartigny M., Morel Y.; RT "p.H62L, a rare mutation of the CYP21 gene identified in two forms of 21- RT hydroxylase deficiency."; RL J. Clin. Endocrinol. Metab. 93:1901-1908(2008). RN [65] RP VARIANTS AH3 ARG-57; LEU-63; ARG-108; PRO-143; ASN-173; TRP-357; CYS-409 RP AND SER-454, AND CHARACTERIZATION OF VARIANTS AH3 ARG-57; LEU-63; ARG-108; RP PRO-143; CYS-409 AND SER-454. RX PubMed=18381579; DOI=10.1210/jc.2007-2594; RA Soardi F.C., Barbaro M., Lau I.F., Lemos-Marini S.H., Baptista M.T., RA Guerra-Junior G., Wedell A., Lajic S., de Mello M.P.; RT "Inhibition of CYP21A2 enzyme activity caused by novel missense mutations RT identified in Brazilian and Scandinavian patients."; RL J. Clin. Endocrinol. Metab. 93:2416-2420(2008). RN [66] RP VARIANTS AH3 GLN-122 AND SER-454, AND CHARACTERIZATION OF VARIANT AH3 RP GLN-122. RX PubMed=18445671; DOI=10.1210/jc.2007-2646; RA Riepe F.G., Hiort O., Grotzinger J., Sippell W.G., Krone N., RA Holterhus P.M.; RT "Functional and structural consequences of a novel point mutation in the RT CYP21A2 gene causing congenital adrenal hyperplasia: potential relevance of RT helix C for P450 oxidoreductase-21-hydroxylase interaction."; RL J. Clin. Endocrinol. Metab. 93:2891-2895(2008). RN [67] RP VARIANTS AH3 THR-78; PRO-168; ASN-173; THR-231; LYS-234; LEU-282; SER-292; RP ASP-293; LYS-321; PRO-342; HIS-355; TRP-357; TRP-370; CYS-409; SER-425; RP HIS-427 AND SER-454, AND CHARACTERIZATION OF VARIANTS AH3 PRO-168; ASN-173; RP LEU-282; ASP-293; LYS-321; TRP-370 AND SER-425. RX PubMed=20080860; DOI=10.1210/jc.2009-1202; RA Tardy V., Menassa R., Sulmont V., Lienhardt-Roussie A., Lecointre C., RA Brauner R., David M., Morel Y.; RT "Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in RT 46 patients affected with 21-hydroxylase deficiency and in one carrier."; RL J. Clin. Endocrinol. Metab. 95:1288-1300(2010). RN [68] RP VARIANT AH3 PHE-199. RX PubMed=21169732; DOI=10.3275/7417; RA Niceta M., Bono M., Fabiano C., Pojero F., Niceta F., Sammarco P., RA Corsello G., Garofalo P.; RT "A large view of CYP21 locus among Sicilians and other populations: RT identification of a novel CYP21A2 variant in Sicily."; RL J. Endocrinol. Invest. 34:847-854(2011). RN [69] RP VARIANTS AH3 HIS-192 AND ASN-283, CHARACTERIZATION OF VARIANTS AH3 HIS-192 RP AND ASN-283, FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=22014889; DOI=10.1016/j.metabol.2011.08.008; RA Concolino P., Mello E., Patrosso M.C., Penco S., Zuppi C., Capoluongo E.; RT "p.H282N and p.Y191H: 2 novel CYP21A2 mutations in Italian congenital RT adrenal hyperplasia patients."; RL Metabolism 61:519-524(2012). RN [70] RP VARIANTS AH3 MET-13; PHE-114; 390-GLN--ALA-392 DEL AND PRO-451, VARIANTS RP CYS-17; GLY-203; LEU-268 AND MET-451, CHARACTERIZATION OF VARIANTS AH3 RP MET-13; PHE-114; 390-GLN--ALA-392 DEL; PRO-451 AND SER-483, RP CHARACTERIZATION OF VARIANTS CYS-17; GLY-203; LEU-268 AND MET-451, RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=27721825; DOI=10.1155/2016/4209670; RA de Paula Michelatto D., Karlsson L., Lusa A.L., Silva C.D., Oestberg L.J., RA Persson B., Guerra-Junior G., de Lemos-Marini S.H., Barbaro M., RA de Mello M.P., Lajic S.; RT "Functional and structural consequences of nine CYP21A2 mutations ranging RT from very mild to severe effects."; RL Int. J. Endocrinol. 2016:4209670-4209670(2016). RN [71] RP VARIANT AH3 TRP-342. RX PubMed=29328376; DOI=10.3892/mmr.2018.8391; RA Liu J., Zhang X., Zhang H., Fang L., Xu J., Guan Q., Xu C.; RT "Identification of a novel compound heterozygous mutation of the CYP21A2 RT gene causing 21-hydroxylase deficiency in a Chinese pedigree."; RL Mol. Med. Report. 17:4265-4272(2018). CC -!- FUNCTION: A cytochrome P450 monooxygenase that plays a major role in CC adrenal steroidogenesis. Catalyzes the hydroxylation at C-21 of CC progesterone and 17alpha-hydroxyprogesterone to respectively form 11- CC deoxycorticosterone and 11-deoxycortisol, intermediate metabolites in CC the biosynthetic pathway of mineralocorticoids and glucocorticoids CC (PubMed:25855791, PubMed:10602386, PubMed:16984992, PubMed:22014889, CC PubMed:27721825). Mechanistically, uses molecular oxygen inserting one CC oxygen atom into a substrate, and reducing the second into a water CC molecule, with two electrons provided by NADPH via cytochrome P450 CC reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:25855791). CC {ECO:0000269|PubMed:10602386, ECO:0000269|PubMed:16984992, CC ECO:0000269|PubMed:22014889, ECO:0000269|PubMed:25855791, CC ECO:0000269|PubMed:27721825}. CC -!- CATALYTIC ACTIVITY: CC Reaction=O2 + progesterone + reduced [NADPH--hemoprotein reductase] = CC 21-hydroxyprogesterone + H(+) + H2O + oxidized [NADPH--hemoprotein CC reductase]; Xref=Rhea:RHEA:50304, Rhea:RHEA-COMP:11964, Rhea:RHEA- CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:16973, ChEBI:CHEBI:17026, ChEBI:CHEBI:57618, CC ChEBI:CHEBI:58210; EC=1.14.14.16; CC Evidence={ECO:0000269|PubMed:16984992, ECO:0000269|PubMed:22014889, CC ECO:0000269|PubMed:25855791, ECO:0000269|PubMed:27721825}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50305; CC Evidence={ECO:0000305|PubMed:16984992, ECO:0000305|PubMed:22014889, CC ECO:0000305|PubMed:25855791, ECO:0000305|PubMed:27721825}; CC -!- CATALYTIC ACTIVITY: CC Reaction=17alpha-hydroxyprogesterone + O2 + reduced [NADPH--hemoprotein CC reductase] = 11-deoxycortisol + H(+) + H2O + oxidized CC [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:50308, Rhea:RHEA- CC COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17252, CC ChEBI:CHEBI:28324, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210; CC EC=1.14.14.16; Evidence={ECO:0000269|PubMed:16984992, CC ECO:0000269|PubMed:22014889, ECO:0000269|PubMed:25855791, CC ECO:0000269|PubMed:27721825}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50309; CC Evidence={ECO:0000305|PubMed:16984992, ECO:0000305|PubMed:22014889, CC ECO:0000305|PubMed:25855791, ECO:0000305|PubMed:27721825}; CC -!- COFACTOR: CC Name=heme b; Xref=ChEBI:CHEBI:60344; CC Evidence={ECO:0000269|PubMed:25855791}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.59 uM for 17alpha-hydroxyprogesterone CC {ECO:0000269|PubMed:22014889}; CC KM=12.5 uM for 17alpha-hydroxyprogesterone (at 37 degrees Celsius) CC {ECO:0000269|PubMed:27721825}; CC KM=1.5 uM for 17alpha-hydroxyprogesterone CC {ECO:0000269|PubMed:25855791}; CC KM=1.05 uM for progesterone {ECO:0000269|PubMed:22014889}; CC KM=0.21 uM for progesterone {ECO:0000269|PubMed:25855791}; CC Vmax=5.8 nmol/min/mg enzyme {ECO:0000269|PubMed:22014889}; CC Vmax=0.5 nmol/min/mg enzyme (at 37 degrees Celsius) CC {ECO:0000269|PubMed:27721825}; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral CC membrane protein {ECO:0000269|PubMed:10198222}. Microsome membrane CC {ECO:0000269|PubMed:10198222}; Peripheral membrane protein CC {ECO:0000269|PubMed:10198222}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P08686-1; Sequence=Displayed; CC Name=2; CC IsoId=P08686-2; Sequence=VSP_062040; CC -!- DOMAIN: The leucine-rich hydrophobic amino acid N-terminal region CC probably helps to anchor the protein to the microsomal membrane. CC {ECO:0000269|PubMed:10198222}. CC -!- POLYMORPHISM: Several non deleterious alleles have been described CC including CYP21A2*1A, CYP21A2*1B, CYP21A2*2, CYP21A2*3, CYP21A2*4, CC CYP21A2*5 and CYP21A2*6. Deleterious alleles are mostly generated by CC recombinations between CYP21A2 and the pseudogene CYP21A1P through gene CC conversion. This process consists of recombination events that either CC delete CYP21A2 or transfer deleterious mutations from CYP21A1P to CC CYP21A2. {ECO:0000303|PubMed:8081391}. CC -!- DISEASE: Adrenal hyperplasia 3 (AH3) [MIM:201910]: A form of congenital CC adrenal hyperplasia, a common recessive disease due to defective CC synthesis of cortisol. Congenital adrenal hyperplasia is characterized CC by androgen excess leading to ambiguous genitalia in affected females, CC rapid somatic growth during childhood in both sexes with premature CC closure of the epiphyses and short adult stature. Four clinical types: CC 'salt wasting' (SW, the most severe type), 'simple virilizing' (SV, CC less severely affected patients), with normal aldosterone biosynthesis, CC 'non-classic form' or late-onset (NC or LOAH) and 'cryptic' CC (asymptomatic). {ECO:0000269|PubMed:10051010, CC ECO:0000269|PubMed:10094562, ECO:0000269|PubMed:10198222, CC ECO:0000269|PubMed:10364682, ECO:0000269|PubMed:10391209, CC ECO:0000269|PubMed:10408778, ECO:0000269|PubMed:10408786, CC ECO:0000269|PubMed:10443693, ECO:0000269|PubMed:10496074, CC ECO:0000269|PubMed:10720040, ECO:0000269|PubMed:11232002, CC ECO:0000269|PubMed:11598371, ECO:0000269|PubMed:11600539, CC ECO:0000269|PubMed:11746135, ECO:0000269|PubMed:12213891, CC ECO:0000269|PubMed:12222711, ECO:0000269|PubMed:12788866, CC ECO:0000269|PubMed:12887291, ECO:0000269|PubMed:12915679, CC ECO:0000269|PubMed:1406699, ECO:0000269|PubMed:1406709, CC ECO:0000269|PubMed:14676460, ECO:0000269|PubMed:14715874, CC ECO:0000269|PubMed:1496017, ECO:0000269|PubMed:15110320, CC ECO:0000269|PubMed:15126570, ECO:0000269|PubMed:16046588, CC ECO:0000269|PubMed:1644925, ECO:0000269|PubMed:16984992, CC ECO:0000269|PubMed:18319307, ECO:0000269|PubMed:18381579, CC ECO:0000269|PubMed:18445671, ECO:0000269|PubMed:1864962, CC ECO:0000269|PubMed:1937474, ECO:0000269|PubMed:20080860, CC ECO:0000269|PubMed:2072928, ECO:0000269|PubMed:21169732, CC ECO:0000269|PubMed:22014889, ECO:0000269|PubMed:2303461, CC ECO:0000269|PubMed:27721825, ECO:0000269|PubMed:29328376, CC ECO:0000269|PubMed:3038528, ECO:0000269|PubMed:3257825, CC ECO:0000269|PubMed:3260007, ECO:0000269|PubMed:3267225, CC ECO:0000269|PubMed:3497399, ECO:0000269|PubMed:3871526, CC ECO:0000269|PubMed:7749410, ECO:0000269|PubMed:8478006, CC ECO:0000269|PubMed:8485582, ECO:0000269|PubMed:8989258, CC ECO:0000269|PubMed:9067760, ECO:0000269|PubMed:9187661, CC ECO:0000269|PubMed:9497336}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M12792; AAB59440.1; -; Genomic_DNA. DR EMBL; M13936; AAA59695.1; -; Genomic_DNA. DR EMBL; M26856; AAA52064.1; -; Genomic_DNA. DR EMBL; X58906; CAA41709.1; -; Genomic_DNA. DR EMBL; GQ222278; ACT35404.1; -; Genomic_DNA. DR EMBL; GQ222283; ACT35409.1; -; Genomic_DNA. DR EMBL; GQ222286; ACT35412.1; -; Genomic_DNA. DR EMBL; GQ222289; ACT35415.1; -; Genomic_DNA. DR EMBL; GQ222296; ACT35422.1; -; Genomic_DNA. DR EMBL; GQ222301; ACT35427.1; -; Genomic_DNA. DR EMBL; GQ222319; ACT35445.1; -; Genomic_DNA. DR EMBL; GQ222295; ACT35421.1; -; Genomic_DNA. DR EMBL; GQ222312; ACT35438.1; -; Genomic_DNA. DR EMBL; GQ222297; ACT35423.1; -; Genomic_DNA. DR EMBL; GQ222320; ACT35446.1; -; Genomic_DNA. DR EMBL; GQ222321; ACT35447.1; -; Genomic_DNA. DR EMBL; GQ222327; ACT35453.1; -; Genomic_DNA. DR EMBL; GQ222323; ACT35449.1; -; Genomic_DNA. DR EMBL; GQ222334; ACT35460.1; -; Genomic_DNA. DR EMBL; GQ222340; ACT35466.1; -; Genomic_DNA. DR EMBL; JN034391; AFK10114.1; -; Genomic_DNA. DR EMBL; JN034393; AFK10116.1; -; Genomic_DNA. DR EMBL; JN034394; AFK10117.1; -; Genomic_DNA. DR EMBL; JN034395; AFK10118.1; -; Genomic_DNA. DR EMBL; JN034396; AFK10119.1; -; Genomic_DNA. DR EMBL; JN034397; AFK10120.1; -; Genomic_DNA. DR EMBL; JN034398; AFK10121.1; -; Genomic_DNA. DR EMBL; JN034401; AFK10124.1; -; Genomic_DNA. DR EMBL; JN034403; AFK10126.1; -; Genomic_DNA. DR EMBL; JN034402; AFK10125.1; -; Genomic_DNA. DR EMBL; JN034410; AFK10133.1; -; Genomic_DNA. DR EMBL; JN034411; AFK10134.1; -; Genomic_DNA. DR EMBL; KC493622; AHA59281.1; -; Genomic_DNA. DR EMBL; KU302773; APT40592.1; -; Genomic_DNA. DR EMBL; KU302772; APT40591.1; -; Genomic_DNA. DR EMBL; AK054616; BAB70774.1; -; mRNA. DR EMBL; AK314651; BAG37212.1; -; mRNA. DR EMBL; AF019413; AAB67982.1; -; Genomic_DNA. DR EMBL; AL049547; CAB89301.1; -; Genomic_DNA. DR EMBL; AL645922; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL662828; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL662849; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL844853; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL929593; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BX679671; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CR753845; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CR936924; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471081; EAX03570.1; -; Genomic_DNA. DR EMBL; CH471081; EAX03571.1; -; Genomic_DNA. DR EMBL; BC125182; AAI25183.1; -; mRNA. DR EMBL; K02771; AAA59706.1; -; Genomic_DNA. DR EMBL; M19711; AAA83248.1; -; Genomic_DNA. DR EMBL; M17252; AAA59985.1; -; mRNA. DR CCDS; CCDS47406.1; -. [P08686-2] DR PIR; A25446; O4HUC2. DR RefSeq; NP_000491.4; NM_000500.7. [P08686-1] DR RefSeq; NP_001122062.3; NM_001128590.3. [P08686-2] DR PDB; 4Y8W; X-ray; 2.64 A; A/B/C=30-495. DR PDB; 5VBU; X-ray; 3.31 A; A/B/C=30-495. DR PDBsum; 4Y8W; -. DR PDBsum; 5VBU; -. DR AlphaFoldDB; P08686; -. DR SMR; P08686; -. DR BioGRID; 107961; 20. DR IntAct; P08686; 2. DR STRING; 9606.ENSP00000496625; -. DR BindingDB; P08686; -. DR ChEMBL; CHEMBL2759; -. DR DrugBank; DB01026; Ketoconazole. DR DrugBank; DB05667; Levoketoconazole. DR DrugCentral; P08686; -. DR SwissLipids; SLP:000001618; -. DR iPTMnet; P08686; -. DR PhosphoSitePlus; P08686; -. DR BioMuta; CYP21A2; -. DR DMDM; 117275; -. DR MassIVE; P08686; -. DR PaxDb; 9606-ENSP00000408860; -. DR PeptideAtlas; P08686; -. DR ProteomicsDB; 52155; -. [P08686-1] DR ProteomicsDB; 61113; -. DR ProteomicsDB; 63894; -. DR Antibodypedia; 53182; 387 antibodies from 28 providers. DR DNASU; 1589; -. DR Ensembl; ENST00000383321.4; ENSP00000372811.4; ENSG00000206338.9. [P08686-2] DR Ensembl; ENST00000383322.8; ENSP00000372812.4; ENSG00000206338.9. [P08686-1] DR Ensembl; ENST00000434026.2; ENSP00000392321.2; ENSG00000232414.6. [P08686-2] DR Ensembl; ENST00000435122.3; ENSP00000415043.2; ENSG00000231852.9. [P08686-2] DR Ensembl; ENST00000436607.6; ENSP00000403721.2; ENSG00000235134.7. DR Ensembl; ENST00000448314.6; ENSP00000398594.2; ENSG00000198457.13. DR Ensembl; ENST00000448478.6; ENSP00000416598.2; ENSG00000232414.6. [P08686-1] DR Ensembl; ENST00000452386.2; ENSP00000403230.2; ENSG00000233151.6. [P08686-2] DR Ensembl; ENST00000456152.6; ENSP00000394942.2; ENSG00000233151.6. [P08686-1] DR Ensembl; ENST00000644719.2; ENSP00000496625.1; ENSG00000231852.9. [P08686-1] DR GeneID; 1589; -. DR KEGG; hsa:1589; -. DR MANE-Select; ENST00000644719.2; ENSP00000496625.1; NM_000500.9; NP_000491.4. DR UCSC; uc003nzf.3; human. [P08686-1] DR AGR; HGNC:2600; -. DR CTD; 1589; -. DR DisGeNET; 1589; -. DR GeneCards; CYP21A2; -. DR GeneReviews; CYP21A2; -. DR HGNC; HGNC:2600; CYP21A2. DR HPA; ENSG00000231852; Tissue enriched (adrenal). DR MalaCards; CYP21A2; -. DR MIM; 201910; phenotype. DR MIM; 613815; gene. DR neXtProt; NX_P08686; -. DR OpenTargets; ENSG00000231852; -. DR Orphanet; 315306; Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form. DR Orphanet; 315311; Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form. DR Orphanet; 95698; NON RARE IN EUROPE: Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. DR PharmGKB; PA27096; -. DR VEuPathDB; HostDB:ENSG00000231852; -. DR eggNOG; KOG0156; Eukaryota. DR GeneTree; ENSGT00940000158338; -. DR HOGENOM; CLU_001570_22_0_1; -. DR InParanoid; P08686; -. DR OMA; VQEFEWG; -. DR OrthoDB; 2900138at2759; -. DR PhylomeDB; P08686; -. DR TreeFam; TF105095; -. DR BioCyc; MetaCyc:HS09769-MONOMER; -. DR BRENDA; 1.14.14.16; 2681. DR PathwayCommons; P08686; -. DR Reactome; R-HSA-193993; Mineralocorticoid biosynthesis. DR Reactome; R-HSA-194002; Glucocorticoid biosynthesis. DR Reactome; R-HSA-211976; Endogenous sterols. DR Reactome; R-HSA-5579021; Defective CYP21A2 causes AH3. DR SignaLink; P08686; -. DR SIGNOR; P08686; -. DR BioGRID-ORCS; 1589; 13 hits in 1141 CRISPR screens. DR ChiTaRS; CYP21A2; human. DR GeneWiki; 21-Hydroxylase; -. DR GenomeRNAi; 1589; -. DR Pharos; P08686; Tchem. DR PRO; PR:P08686; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; P08686; Protein. DR Bgee; ENSG00000231852; Expressed in right adrenal gland and 92 other cell types or tissues. DR ExpressionAtlas; P08686; baseline and differential. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. DR GO; GO:0103069; F:17-hydroxyprogesterone 21-hydroxylase activity; IDA:UniProtKB. DR GO; GO:0020037; F:heme binding; IDA:UniProtKB. DR GO; GO:0005506; F:iron ion binding; IEA:InterPro. DR GO; GO:0106309; F:progesterone 21-hydroxylase activity; IDA:UniProtKB. DR GO; GO:0004509; F:steroid 21-monooxygenase activity; IBA:GO_Central. DR GO; GO:0005496; F:steroid binding; IEA:UniProtKB-KW. DR GO; GO:0008395; F:steroid hydroxylase activity; IMP:UniProtKB. DR GO; GO:0006704; P:glucocorticoid biosynthetic process; IBA:GO_Central. DR GO; GO:0006705; P:mineralocorticoid biosynthetic process; TAS:Reactome. DR GO; GO:0006694; P:steroid biosynthetic process; IDA:UniProtKB. DR GO; GO:0008202; P:steroid metabolic process; IMP:UniProtKB. DR GO; GO:0016125; P:sterol metabolic process; TAS:Reactome. DR CDD; cd20674; CYP21; 1. DR Gene3D; 1.10.630.10; Cytochrome P450; 1. DR InterPro; IPR001128; Cyt_P450. DR InterPro; IPR017972; Cyt_P450_CS. DR InterPro; IPR002401; Cyt_P450_E_grp-I. DR InterPro; IPR036396; Cyt_P450_sf. DR PANTHER; PTHR24289; STEROID 17-ALPHA-HYDROXYLASE/17,20 LYASE; 1. DR PANTHER; PTHR24289:SF14; STEROID 21-HYDROXYLASE-LIKE; 1. DR Pfam; PF00067; p450; 1. DR PRINTS; PR00463; EP450I. DR PRINTS; PR00385; P450. DR SUPFAM; SSF48264; Cytochrome P450; 1. DR PROSITE; PS00086; CYTOCHROME_P450; 1. DR Genevisible; P08686; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Congenital adrenal hyperplasia; KW Disease variant; Endoplasmic reticulum; Heme; Iron; Lipid metabolism; KW Lipid-binding; Membrane; Metal-binding; Microsome; Monooxygenase; KW Oxidoreductase; Reference proteome; Steroid-binding; Steroidogenesis. FT CHAIN 1..495 FT /note="Steroid 21-hydroxylase" FT /id="PRO_0000051976" FT BINDING 92 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /evidence="ECO:0000269|PubMed:25855791, FT ECO:0007744|PDB:4Y8W" FT BINDING 121 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /evidence="ECO:0000269|PubMed:25855791, FT ECO:0007744|PDB:4Y8W" FT BINDING 234 FT /ligand="17alpha-hydroxyprogesterone" FT /ligand_id="ChEBI:CHEBI:17252" FT /evidence="ECO:0000250|UniProtKB:P00191" FT BINDING 234 FT /ligand="progesterone" FT /ligand_id="ChEBI:CHEBI:17026" FT /evidence="ECO:0000269|PubMed:25855791, FT ECO:0007744|PDB:4Y8W" FT BINDING 366 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /evidence="ECO:0000269|PubMed:25855791, FT ECO:0007744|PDB:4Y8W" FT BINDING 427 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /evidence="ECO:0000269|PubMed:25855791, FT ECO:0007744|PDB:4Y8W" FT BINDING 429 FT /ligand="heme b" FT /ligand_id="ChEBI:CHEBI:60344" FT /ligand_part="Fe" FT /ligand_part_id="ChEBI:CHEBI:18248" FT /note="axial binding residue" FT /evidence="ECO:0000269|PubMed:25855791, FT ECO:0007744|PDB:4Y8W" FT VAR_SEQ 69..98 FT /note="Missing (in isoform 2)" FT /id="VSP_062040" FT VARIANT 6 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:19505723, FT ECO:0000269|PubMed:3486422, ECO:0000269|PubMed:3487786" FT /id="VAR_088451" FT VARIANT 13 FT /note="L -> M (in AH3; uncertain significance; non-classic FT form; no effect on steroid 21-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:27721825" FT /id="VAR_077582" FT VARIANT 16 FT /note="A -> T (in AH3; uncertain significance; salt wasting FT form; no significant difference in steroid 21-monooxygenase FT activity; dbSNP:rs63749090)" FT /evidence="ECO:0000269|PubMed:12887291, FT ECO:0000269|PubMed:15126570" FT /id="VAR_026059" FT VARIANT 17 FT /note="R -> C (decreased steroid 21-monooxygenase activity; FT dbSNP:rs757608533)" FT /evidence="ECO:0000269|PubMed:27721825" FT /id="VAR_077583" FT VARIANT 31 FT /note="P -> L (in AH3; non-classic form; 50% steroid FT 21-monooxygenase activity; dbSNP:rs9378251)" FT /evidence="ECO:0000269|PubMed:10364682, FT ECO:0000269|PubMed:10408778, ECO:0000269|PubMed:10408786, FT ECO:0000269|PubMed:10496074, ECO:0000269|PubMed:10720040, FT ECO:0000269|PubMed:11232002, ECO:0000269|PubMed:11598371, FT ECO:0000269|PubMed:11600539, ECO:0000269|PubMed:12222711, FT ECO:0000269|PubMed:12788866, ECO:0000269|PubMed:12887291, FT ECO:0000269|PubMed:15110320, ECO:0000269|PubMed:15126570, FT ECO:0000269|PubMed:16046588, ECO:0000269|PubMed:1644925, FT ECO:0000269|PubMed:18319307, ECO:0000269|PubMed:2072928" FT /id="VAR_001281" FT VARIANT 31 FT /note="P -> Q (in AH3; does not affect membrane binding; FT enzyme function abolished)" FT /evidence="ECO:0000269|PubMed:10198222" FT /id="VAR_026060" FT VARIANT 57 FT /note="G -> R (in AH3; loss of activity; FT dbSNP:rs1413433421)" FT /evidence="ECO:0000269|PubMed:18381579" FT /id="VAR_065668" FT VARIANT 63 FT /note="H -> L (in AH3; non-classic form; simple virilizing FT form when associated with a second mild mutation such as FT S-453 or L-30; activity is significantly reduced in FT association with S-453; dbSNP:rs9378252)" FT /evidence="ECO:0000269|PubMed:12788866, FT ECO:0000269|PubMed:18319307, ECO:0000269|PubMed:18381579" FT /id="VAR_018364" FT VARIANT 65 FT /note="G -> E (in AH3; no activity)" FT /evidence="ECO:0000269|PubMed:10408778" FT /id="VAR_007923" FT VARIANT 78 FT /note="I -> T (in AH3; simple virilizing form; FT dbSNP:rs1333278223)" FT /evidence="ECO:0000269|PubMed:20080860" FT /id="VAR_065669" FT VARIANT 91 FT /note="G -> V (in AH3)" FT /evidence="ECO:0000269|PubMed:10364682" FT /id="VAR_026061" FT VARIANT 99 FT /note="K -> R (in dbSNP:rs1268071078)" FT /evidence="ECO:0000269|PubMed:9580109" FT /id="VAR_001282" FT VARIANT 103 FT /note="R -> K (in dbSNP:rs6474)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:19505723, ECO:0000269|PubMed:3038528, FT ECO:0000269|PubMed:3486422, ECO:0000269|PubMed:9580109" FT /id="VAR_001283" FT VARIANT 106 FT /note="P -> L (in AH3; dbSNP:rs550051210)" FT /evidence="ECO:0000269|PubMed:1496017, FT ECO:0000269|PubMed:8989258" FT /id="VAR_001284" FT VARIANT 108 FT /note="L -> R (in AH3; loss of activity; FT dbSNP:rs957886272)" FT /evidence="ECO:0000269|PubMed:18381579" FT /id="VAR_065670" FT VARIANT 114 FT /note="S -> F (in AH3; non-classic form; loss of steroid FT 21-monooxygenase activity; dbSNP:rs1296268275)" FT /evidence="ECO:0000269|PubMed:27721825" FT /id="VAR_077584" FT VARIANT 122 FT /note="K -> Q (in AH3; non-classic form; reduced activity; FT decreased affinity for 17-hydroxyprogesterone and FT progesterone; dbSNP:rs547552654)" FT /evidence="ECO:0000269|PubMed:18445671" FT /id="VAR_065671" FT VARIANT 125 FT /note="R -> H (in AH3; dbSNP:rs72552750)" FT /evidence="ECO:0000269|PubMed:14676460" FT /id="VAR_026062" FT VARIANT 143 FT /note="L -> P (in AH3; loss of activity; FT dbSNP:rs755020999)" FT /evidence="ECO:0000269|PubMed:18381579" FT /id="VAR_065672" FT VARIANT 168 FT /note="L -> P (in AH3; salt wasting form; loss of FT activity)" FT /evidence="ECO:0000269|PubMed:20080860" FT /id="VAR_065673" FT VARIANT 170 FT /note="C -> R (in AH3; loss of hydroxylase activity toward FT 17-hydroxyprogesterone and progesterone)" FT /evidence="ECO:0000269|PubMed:16984992" FT /id="VAR_075372" FT VARIANT 170 FT /note="C -> Y (in AH3)" FT /evidence="ECO:0000269|PubMed:10094562" FT /id="VAR_001285" FT VARIANT 173 FT /note="I -> N (in AH3; simple virilizing form; 1-4% FT activity; dbSNP:rs6475)" FT /evidence="ECO:0000269|PubMed:10051010, FT ECO:0000269|PubMed:10364682, ECO:0000269|PubMed:10408778, FT ECO:0000269|PubMed:10408786, ECO:0000269|PubMed:10496074, FT ECO:0000269|PubMed:10720040, ECO:0000269|PubMed:11232002, FT ECO:0000269|PubMed:11598371, ECO:0000269|PubMed:11600539, FT ECO:0000269|PubMed:12222711, ECO:0000269|PubMed:12788866, FT ECO:0000269|PubMed:12887291, ECO:0000269|PubMed:12915679, FT ECO:0000269|PubMed:14715874, ECO:0000269|PubMed:15110320, FT ECO:0000269|PubMed:16046588, ECO:0000269|PubMed:1644925, FT ECO:0000269|PubMed:18319307, ECO:0000269|PubMed:18381579, FT ECO:0000269|PubMed:1937474, ECO:0000269|PubMed:20080860, FT ECO:0000269|PubMed:2303461, ECO:0000269|PubMed:3257825, FT ECO:0000269|PubMed:3871526, ECO:0000269|PubMed:7749410, FT ECO:0000269|PubMed:8485582" FT /id="VAR_001286" FT VARIANT 179 FT /note="G -> A (in AH3; dbSNP:rs72552751)" FT /evidence="ECO:0000269|PubMed:10364682" FT /id="VAR_026063" FT VARIANT 179 FT /note="G -> R (in AH3; loss of enzymatic activity toward FT 17-hydroxyprogesterone and progesterone; FT dbSNP:rs772317717)" FT /evidence="ECO:0000269|PubMed:16984992" FT /id="VAR_075373" FT VARIANT 184 FT /note="D -> E (in allele CYP21A2*4; dbSNP:rs397515531)" FT /evidence="ECO:0000269|PubMed:9580109" FT /id="VAR_001287" FT VARIANT 192 FT /note="Y -> H (in AH3; exhibits low enzymatic activity FT toward 17-hydroxyprogesterone and progesterone)" FT /evidence="ECO:0000269|PubMed:22014889" FT /id="VAR_075374" FT VARIANT 197 FT /note="Missing (in AH3; moderate)" FT /evidence="ECO:0000269|PubMed:9497336" FT /id="VAR_008688" FT VARIANT 199 FT /note="L -> F (in AH3; dbSNP:rs143240527)" FT /evidence="ECO:0000269|PubMed:21169732" FT /id="VAR_075375" FT VARIANT 203 FT /note="S -> G (decreased steroid 21-monooxygenase activity; FT dbSNP:rs372964292)" FT /evidence="ECO:0000269|PubMed:27721825" FT /id="VAR_077585" FT VARIANT 212 FT /note="V -> L (in AH3; uncertain significance; non-classic FT form)" FT /evidence="ECO:0000269|PubMed:3260007" FT /id="VAR_026064" FT VARIANT 231 FT /note="I -> T (in AH3)" FT /evidence="ECO:0000269|PubMed:20080860" FT /id="VAR_065674" FT VARIANT 234 FT /note="R -> K (in AH3)" FT /evidence="ECO:0000269|PubMed:20080860" FT /id="VAR_065675" FT VARIANT 237 FT /note="I -> N (in AH3; salt wasting form; FT dbSNP:rs111647200)" FT /evidence="ECO:0000269|PubMed:10408778, FT ECO:0000269|PubMed:10408786, ECO:0000269|PubMed:15110320, FT ECO:0000269|PubMed:1644925, ECO:0000269|PubMed:7749410" FT /id="VAR_001288" FT VARIANT 238 FT /note="V -> E (in AH3; salt wasting form; FT dbSNP:rs12530380)" FT /evidence="ECO:0000269|PubMed:10408786, FT ECO:0000269|PubMed:15110320, ECO:0000269|PubMed:1644925" FT /id="VAR_001289" FT VARIANT 240 FT /note="M -> K (in AH3; salt wasting form; dbSNP:rs6476)" FT /evidence="ECO:0000269|PubMed:10408786, FT ECO:0000269|PubMed:15110320, ECO:0000269|PubMed:1644925" FT /id="VAR_001290" FT VARIANT 262 FT /note="L -> P (in AH3; dbSNP:rs750337015)" FT /evidence="ECO:0000269|PubMed:11598371" FT /id="VAR_026065" FT VARIANT 268 FT /note="P -> L (decreased steroid 21-monooxygenase activity; FT dbSNP:rs61732108 and dbSNP:rs142028935)" FT /evidence="ECO:0000269|PubMed:27721825" FT /id="VAR_077586" FT VARIANT 269 FT /note="S -> T (in allele CYP21A2*5; dbSNP:rs6472)" FT /evidence="ECO:0000269|PubMed:10391209, FT ECO:0000269|PubMed:10496074, ECO:0000269|PubMed:2072928, FT ECO:0000269|PubMed:3038528" FT /id="VAR_001291" FT VARIANT 282 FT /note="V -> G (in AH3; salt wasting form)" FT /evidence="ECO:0000269|PubMed:10720040" FT /id="VAR_026066" FT VARIANT 282 FT /note="V -> L (in AH3; non-classic form; 50% activity; most FT common variant; normal KM but 20% reduced Vmax; FT dbSNP:rs6471)" FT /evidence="ECO:0000269|PubMed:10094562, FT ECO:0000269|PubMed:10364682, ECO:0000269|PubMed:10391209, FT ECO:0000269|PubMed:10408778, ECO:0000269|PubMed:10408786, FT ECO:0000269|PubMed:10443693, ECO:0000269|PubMed:10496074, FT ECO:0000269|PubMed:10720040, ECO:0000269|PubMed:11232002, FT ECO:0000269|PubMed:11600539, ECO:0000269|PubMed:12222711, FT ECO:0000269|PubMed:12788866, ECO:0000269|PubMed:12887291, FT ECO:0000269|PubMed:12915679, ECO:0000269|PubMed:15110320, FT ECO:0000269|PubMed:15126570, ECO:0000269|PubMed:1644925, FT ECO:0000269|PubMed:1864962, ECO:0000269|PubMed:20080860, FT ECO:0000269|PubMed:3260007, ECO:0000269|PubMed:3267225, FT ECO:0000269|PubMed:3497399, ECO:0000269|PubMed:7749410" FT /id="VAR_001292" FT VARIANT 283 FT /note="H -> N (in AH3; exhibits low enzymatic activity FT toward 17-hydroxyprogesterone and progesterone)" FT /evidence="ECO:0000269|PubMed:22014889" FT /id="VAR_075376" FT VARIANT 284 FT /note="M -> L (in AH3)" FT /evidence="ECO:0000269|PubMed:12222711" FT /id="VAR_026067" FT VARIANT 292 FT /note="G -> C (in AH3)" FT /evidence="ECO:0000269|PubMed:10364682" FT /id="VAR_026068" FT VARIANT 292 FT /note="G -> R (in AH3; dbSNP:rs201552310)" FT /evidence="ECO:0000269|PubMed:12915679" FT /id="VAR_018365" FT VARIANT 292 FT /note="G -> S (in AH3; salt wasting form; less then 1% FT activity; dbSNP:rs201552310)" FT /evidence="ECO:0000269|PubMed:10408778, FT ECO:0000269|PubMed:11600539, ECO:0000269|PubMed:1496017, FT ECO:0000269|PubMed:15110320, ECO:0000269|PubMed:20080860, FT ECO:0000269|PubMed:9497336" FT /id="VAR_001293" FT VARIANT 293 FT /note="G -> D (in AH3; salt wasting form; less then 1% FT activity)" FT /evidence="ECO:0000269|PubMed:20080860" FT /id="VAR_065676" FT VARIANT 301 FT /note="L -> F (in AH3; salt wasting form; FT dbSNP:rs765001985)" FT /evidence="ECO:0000269|PubMed:10720040" FT /id="VAR_026069" FT VARIANT 302 FT /note="S -> Y (in AH3)" FT /evidence="ECO:0000269|PubMed:12915679" FT /id="VAR_018366" FT VARIANT 303 FT /note="W -> R (in AH3; loss of enzymatic activity toward FT 17-hydroxyprogesterone and progesterone)" FT /evidence="ECO:0000269|PubMed:16984992" FT /id="VAR_075377" FT VARIANT 305 FT /note="V -> M (in hyperandrogenism; due to 21-hydroxylase FT deficiency; non-classic type; residual activity of 46% for FT conversion of 17-hydroxyprogesterone and 26% for conversion FT of progesterone compared with the normal enzyme; FT dbSNP:rs151344505)" FT /evidence="ECO:0000269|PubMed:12050257" FT /id="VAR_026070" FT VARIANT 318 FT /note="L -> M (in AH3)" FT /evidence="ECO:0000269|PubMed:11232002" FT /id="VAR_026071" FT VARIANT 321 FT /note="E -> K (in AH3; simple virilizing form; 4% FT activity)" FT /evidence="ECO:0000269|PubMed:20080860" FT /id="VAR_065677" FT VARIANT 340 FT /note="R -> H (in AH3; non-classic form; 50% activity; FT dbSNP:rs72552754)" FT /evidence="ECO:0000269|PubMed:1406709" FT /id="VAR_001294" FT VARIANT 342 FT /note="R -> P (in AH3; simple virilizing form; FT dbSNP:rs747079101)" FT /evidence="ECO:0000269|PubMed:12788866, FT ECO:0000269|PubMed:20080860" FT /id="VAR_018367" FT VARIANT 342 FT /note="R -> W (in AH3; non-classic form; mild; FT dbSNP:rs72552755)" FT /evidence="ECO:0000269|PubMed:29328376" FT /id="VAR_001295" FT VARIANT 355 FT /note="R -> C (in AH3; salt wasting form; FT dbSNP:rs772900496)" FT /evidence="ECO:0000269|PubMed:10720040" FT /id="VAR_026072" FT VARIANT 355 FT /note="R -> H (in AH3; salt wasting form; FT dbSNP:rs760216630)" FT /evidence="ECO:0000269|PubMed:10364682, FT ECO:0000269|PubMed:20080860" FT /id="VAR_026073" FT VARIANT 357 FT /note="R -> P (in AH3; salt wasting form; 0.15% activity)" FT /evidence="ECO:0000269|PubMed:9187661" FT /id="VAR_001296" FT VARIANT 357 FT /note="R -> Q (in AH3; simple virilizing form; mild; 0.65% FT activity; dbSNP:rs574370139)" FT /evidence="ECO:0000269|PubMed:10094562, FT ECO:0000269|PubMed:15110320, ECO:0000269|PubMed:9187661" FT /id="VAR_001297" FT VARIANT 357 FT /note="R -> W (in AH3; salt wasting form; dbSNP:rs7769409)" FT /evidence="ECO:0000269|PubMed:10051010, FT ECO:0000269|PubMed:10364682, ECO:0000269|PubMed:10408778, FT ECO:0000269|PubMed:10408786, ECO:0000269|PubMed:10443693, FT ECO:0000269|PubMed:10496074, ECO:0000269|PubMed:10720040, FT ECO:0000269|PubMed:11232002, ECO:0000269|PubMed:11598371, FT ECO:0000269|PubMed:11600539, ECO:0000269|PubMed:12222711, FT ECO:0000269|PubMed:12788866, ECO:0000269|PubMed:12915679, FT ECO:0000269|PubMed:14715874, ECO:0000269|PubMed:15110320, FT ECO:0000269|PubMed:16046588, ECO:0000269|PubMed:1644925, FT ECO:0000269|PubMed:18319307, ECO:0000269|PubMed:18381579, FT ECO:0000269|PubMed:20080860, ECO:0000269|PubMed:2303461" FT /id="VAR_001298" FT VARIANT 363 FT /note="A -> V (in AH3; no activity)" FT /evidence="ECO:0000269|PubMed:10408778" FT /id="VAR_007924" FT VARIANT 364 FT /note="L -> W (in AH3)" FT /evidence="ECO:0000269|PubMed:11746135" FT /id="VAR_026074" FT VARIANT 366 FT /note="H -> Y (in AH3; dbSNP:rs1330554738)" FT /evidence="ECO:0000269|PubMed:15110320" FT /id="VAR_026075" FT VARIANT 370 FT /note="R -> W (in AH3; dbSNP:rs781074931)" FT /evidence="ECO:0000269|PubMed:20080860" FT /id="VAR_065678" FT VARIANT 376 FT /note="G -> S (in hyperandrogenism; due to 21-hydroxylase FT deficiency; almost completely abolished enzyme activity; FT dbSNP:rs151344506)" FT /evidence="ECO:0000269|PubMed:12050257" FT /id="VAR_026076" FT VARIANT 381 FT /note="E -> D (in AH3; salt wasting form; FT dbSNP:rs72552756)" FT /evidence="ECO:0000269|PubMed:9067760" FT /id="VAR_001299" FT VARIANT 390..392 FT /note="Missing (in AH3; salt wasting form; loss of steroid FT 21-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:27721825" FT /id="VAR_077587" FT VARIANT 409 FT /note="R -> C (in AH3; very low residual activity; FT dbSNP:rs72552757)" FT /evidence="ECO:0000269|PubMed:12213891, FT ECO:0000269|PubMed:18381579, ECO:0000269|PubMed:20080860" FT /id="VAR_026077" FT VARIANT 425 FT /note="G -> S (in AH3; very low activity; FT dbSNP:rs72552758)" FT /evidence="ECO:0000269|PubMed:10443693, FT ECO:0000269|PubMed:11600539, ECO:0000269|PubMed:12213891, FT ECO:0000269|PubMed:20080860" FT /id="VAR_026078" FT VARIANT 427 FT /note="R -> C (in AH3; loss of enzymatic activity toward FT 17-hydroxyprogesterone and progesterone; FT dbSNP:rs1370167869)" FT /evidence="ECO:0000269|PubMed:16984992" FT /id="VAR_075378" FT VARIANT 427 FT /note="R -> H (in AH3; loss of enzymatic activity toward FT 17-hydroxyprogesterone; dbSNP:rs151344504)" FT /evidence="ECO:0000269|PubMed:11600539, FT ECO:0000269|PubMed:16984992, ECO:0000269|PubMed:20080860" FT /id="VAR_026079" FT VARIANT 436 FT /note="R -> C (in AH3; dbSNP:rs767333157)" FT /evidence="ECO:0000269|PubMed:11232002" FT /id="VAR_026080" FT VARIANT 451 FT /note="T -> M (decreased steroid 21-monooxygenase activity; FT dbSNP:rs1319651744)" FT /evidence="ECO:0000269|PubMed:27721825" FT /id="VAR_077588" FT VARIANT 451 FT /note="T -> P (in AH3; salt wasting form; loss of steroid FT 21-monooxygenase activity)" FT /evidence="ECO:0000269|PubMed:27721825" FT /id="VAR_077589" FT VARIANT 454 FT /note="P -> S (in AH3; non-classic form; simple virilizing FT form when associated with L-62; 50% of activity; almost FT completely abolished enzyme activity when associated with FT S-375; dbSNP:rs6445)" FT /evidence="ECO:0000269|PubMed:10364682, FT ECO:0000269|PubMed:10391209, ECO:0000269|PubMed:10720040, FT ECO:0000269|PubMed:11232002, ECO:0000269|PubMed:11600539, FT ECO:0000269|PubMed:12050257, ECO:0000269|PubMed:12222711, FT ECO:0000269|PubMed:12788866, ECO:0000269|PubMed:12887291, FT ECO:0000269|PubMed:1406699, ECO:0000269|PubMed:1406709, FT ECO:0000269|PubMed:1496017, ECO:0000269|PubMed:15110320, FT ECO:0000269|PubMed:18319307, ECO:0000269|PubMed:18381579, FT ECO:0000269|PubMed:18445671, ECO:0000269|PubMed:20080860, FT ECO:0000269|PubMed:8989258" FT /id="VAR_001300" FT VARIANT 480 FT /note="R -> L (in AH3; dbSNP:rs184649564)" FT /evidence="ECO:0000269|PubMed:15110320" FT /id="VAR_026081" FT VARIANT 483 FT /note="P -> S (in AH3; reduced enzyme activity to 70% of FT normal; dbSNP:rs776989258)" FT /evidence="ECO:0000269|PubMed:15126570, FT ECO:0000269|PubMed:27721825" FT /id="VAR_026082" FT VARIANT 484 FT /note="R -> P (in AH3; moderate; 1-2% of activity; FT dbSNP:rs200005406)" FT /evidence="ECO:0000269|PubMed:11598371, FT ECO:0000269|PubMed:11600539, ECO:0000269|PubMed:12788866, FT ECO:0000269|PubMed:15110320, ECO:0000269|PubMed:7749410, FT ECO:0000269|PubMed:8478006, ECO:0000269|PubMed:9497336" FT /id="VAR_001301" FT VARIANT 484 FT /note="R -> Q (in AH3; dbSNP:rs200005406)" FT /evidence="ECO:0000269|PubMed:12915679" FT /id="VAR_018368" FT VARIANT 484 FT /note="R -> W (in AH3; salt wasting form; FT dbSNP:rs759736443)" FT /evidence="ECO:0000269|PubMed:14715874" FT /id="VAR_026083" FT VARIANT 494 FT /note="S -> N (in dbSNP:rs6473)" FT /evidence="ECO:0000269|PubMed:19505723, FT ECO:0000269|PubMed:3038528, ECO:0000269|PubMed:3486422, FT ECO:0000269|PubMed:3487786, ECO:0000269|PubMed:3497399, FT ECO:0000269|PubMed:9580109" FT /id="VAR_001302" FT MUTAGEN 269 FT /note="S->C,M,T: No effect on progesterone 21-hydroxylase FT activity." FT /evidence="ECO:0000269|PubMed:1864962" FT MUTAGEN 282 FT /note="V->I: Decreased 21-hydroxylase activity. Normal KM FT but 50% reduced Vmax." FT /evidence="ECO:0000269|PubMed:1864962" FT MUTAGEN 282 FT /note="V->T: Decreased 21-hydroxylase activity. Normal KM FT but 10% reduced Vmax." FT /evidence="ECO:0000269|PubMed:1864962" FT MUTAGEN 429 FT /note="C->M,S,T: Loss of progesterone 21-hydroxylase FT activity and loss of P450 absorption." FT /evidence="ECO:0000269|PubMed:1864962" FT CONFLICT 156 FT /note="G -> D (in Ref. 10; BAB70774)" FT /evidence="ECO:0000305" FT CONFLICT 243 FT /note="R -> G (in Ref. 10; BAB70774)" FT /evidence="ECO:0000305" FT CONFLICT 278 FT /note="L -> Q (in Ref. 10; BAB70774)" FT /evidence="ECO:0000305" FT CONFLICT 305 FT /note="V -> A (in Ref. 10; BAB70774)" FT /evidence="ECO:0000305" FT CONFLICT 312 FT /note="P -> L (in Ref. 18; AAA59985)" FT /evidence="ECO:0000305" FT CONFLICT 347 FT /note="N -> I (in Ref. 18; AAA59985)" FT /evidence="ECO:0000305" FT CONFLICT 427 FT /note="R -> P (in Ref. 1; AAB59440)" FT /evidence="ECO:0000305" FT CONFLICT 438 FT /note="E -> D (in Ref. 1; AAB59440)" FT /evidence="ECO:0000305" FT STRAND 32..36 FT /evidence="ECO:0007829|PDB:5VBU" FT HELIX 38..40 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 41..43 FT /evidence="ECO:0007829|PDB:5VBU" FT HELIX 44..50 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 52..55 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 57..63 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 66..71 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 74..81 FT /evidence="ECO:0007829|PDB:4Y8W" FT TURN 82..84 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 85..88 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 95..99 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 102..104 FT /evidence="ECO:0007829|PDB:5VBU" FT HELIX 114..128 FT /evidence="ECO:0007829|PDB:4Y8W" FT TURN 129..134 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 135..150 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 153..155 FT /evidence="ECO:0007829|PDB:5VBU" FT HELIX 160..177 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 179..182 FT /evidence="ECO:0007829|PDB:4Y8W" FT TURN 183..185 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 187..201 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 204..211 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 213..216 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 223..245 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 256..261 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 278..309 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 311..324 FT /evidence="ECO:0007829|PDB:4Y8W" FT TURN 336..338 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 343..355 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 369..373 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 376..378 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 383..386 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 388..392 FT /evidence="ECO:0007829|PDB:4Y8W" FT TURN 395..397 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 398..400 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 406..409 FT /evidence="ECO:0007829|PDB:4Y8W" FT HELIX 424..426 FT /evidence="ECO:0007829|PDB:5VBU" FT HELIX 431..446 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 449..457 FT /evidence="ECO:0007829|PDB:4Y8W" FT STRAND 478..482 FT /evidence="ECO:0007829|PDB:4Y8W" SQ SEQUENCE 495 AA; 56001 MW; CE5C4EE9D3A0851C CRC64; MLLLGLLLLL PLLAGARLLW NWWKLRSLHL PPLAPGFLHL LQPDLPIYLL GLTQKFGPIY RLHLGLQDVV VLNSKRTIEE AMVKKWADFA GRPEPLTYKL VSRNYPDLSL GDYSLLWKAH KKLTRSALLL GIRDSMEPVV EQLTQEFCER MRAQPGTPVA IEEEFSLLTC SIICYLTFGD KIKDDNLMPA YYKCIQEVLK TWSHWSIQIV DVIPFLRFFP NPGLRRLKQA IEKRDHIVEM QLRQHKESLV AGQWRDMMDY MLQGVAQPSM EEGSGQLLEG HVHMAAVDLL IGGTETTANT LSWAVVFLLH HPEIQQRLQE ELDHELGPGA SSSRVPYKDR ARLPLLNATI AEVLRLRPVV PLALPHRTTR PSSISGYDIP EGTVIIPNLQ GAHLDETVWE RPHEFWPDRF LEPGKNSRAL AFGCGARVCL GEPLARLELF VVLTRLLQAF TLLPSGDALP SLQPLPHCSV ILKMQPFQVR LQPRGMGAHS PGQSQ //