CP21A_HUMAN
ID CP21A_HUMAN Reviewed; 494 AA.
AC P08686; A2BHY6; P04033; Q01204; Q08AG8; Q16749; Q16806; Q5ST44; Q96NU8;
DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1988, sequence version 1.
DT 03-AUG-2022, entry version 233.
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).
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).
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-268, VARIANTS LEU-9 INS;
RP ARG-102 AND SER-493, 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], VARIANT AH3 LEU-281, AND VARIANT LEU-9
RP INS.
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], VARIANTS LEU-9 INS; ARG-102 AND SER-493,
RP AND VARIANTS AH3 HIS-339 AND SER-453.
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].
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 [LARGE SCALE MRNA] (ALLELE CYP21A2*6) (ISOFORM 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 [8]
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 [9]
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT SER-493.
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 [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 109-185, AND VARIANT AH3 ASN-172.
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 [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 149-182, AND VARIANT AH3 ASN-172.
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 [13]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 149-182, AND VARIANT AH3 ASN-172.
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 [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 265-494 (ISOFORM 1), AND VARIANT AH3 LEU-281.
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 [15]
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 [16] {ECO:0007744|PDB:4Y8W}
RP X-RAY CRYSTALLOGRAPHY (2.64 ANGSTROMS) OF 29-494 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 [17]
RP CHARACTERIZATION OF VARIANT AH3 LEU-281, AND MUTAGENESIS OF SER-268 AND
RP CYS-428.
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 [18]
RP REVIEW ON AH3 VARIANTS.
RA Gunn S.K., Sherman L.D., Therrell B.L., Owerbach D.I.;
RT "Molecular genetics of 21-hydroxylase deficient late-onset adrenal
RT hyperplasia.";
RL Semin. Reprod. Endocrinol. 11:347-352(1993).
RN [19]
RP REVIEW ON AH3 VARIANTS, AND GENE CONVERSION.
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 [20]
RP VARIANTS AH3 LEU-211 AND LEU-281.
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 [21]
RP VARIANTS AH3 ASN-172 AND TRP-356, AND VARIANT LEU-9 INS.
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 [22]
RP VARIANT AH3 ASN-172.
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 [23]
RP VARIANT AH3 LEU-30, AND VARIANT THR-268.
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 [24]
RP VARIANTS AH3 LEU-30; ASN-172; ASN-236; GLU-237; LYS-239; LEU-281 AND
RP TRP-356.
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 [25]
RP VARIANT AH3 SER-453.
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 [26]
RP VARIANTS AH3 LEU-105; SER-291 AND SER-453.
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 [27]
RP VARIANT AH3 PRO-483.
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 [28]
RP VARIANTS AH3 ASN-172; ASN-236; LEU-281 AND PRO-483, AND VARIANT SER-493.
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 [29]
RP VARIANT AH3 ASP-380.
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 [30]
RP VARIANTS AH3 PRO-356 AND GLN-356.
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 [31]
RP VARIANTS AH3 LEU-105 AND SER-453.
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 [32]
RP VARIANTS AH3, AND VARIANTS.
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 [33]
RP VARIANTS AH3 GLU-196 DEL; SER-291 AND PRO-483.
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 [34]
RP VARIANT AH3 GLN-30, CHARACTERIZATION OF VARIANT AH3 GLN-30, 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 [35]
RP VARIANTS AH3 LEU-30; VAL-90; ASN-172; ALA-178; LEU-281; CYS-291; HIS-354;
RP TRP-356 AND SER-453.
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 [36]
RP VARIANTS AH3 TYR-169; LEU-281 AND GLN-356.
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 [37]
RP VARIANTS AH3 LEU-30; GLU-64; ASN-172; ASN-236; LEU-281; SER-291; TRP-356
RP AND VAL-362.
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 [38]
RP VARIANTS AH3 LEU-30; ASN-172; ASN-236; GLU-237; LYS-239; LEU-281 AND
RP TRP-356.
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 [39]
RP VARIANTS AH3 LEU-281; TRP-356 AND SER-424.
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 [40]
RP VARIANTS AH3 LEU-30; ASN-172; LEU-281; TRP-356 AND SER-493, AND VARIANT
RP THR-268.
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 [41]
RP VARIANTS AH3 ASN-172 AND TRP-356.
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 [42]
RP VARIANTS AH3 LEU-281 AND SER-453, AND VARIANTS THR-268 AND SER-493.
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 [43]
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 [44]
RP VARIANTS AH3 LEU-30; ASN-172; LEU-281; GLY-281; PHE-300; CYS-354; TRP-356
RP AND SER-453.
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 [45]
RP VARIANTS AH3 LEU-30; ASN-172; PRO-261; TRP-356 AND PRO-483.
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 [46]
RP VARIANTS AH3 LEU-30; ASN-172; LEU-281; MET-317; TRP-356; CYS-435 AND
RP SER-453.
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 [47]
RP VARIANTS AH3 LEU-30; ASN-172; LEU-281; SER-291; TRP-356; SER-424; HIS-426;
RP SER-453 AND PRO-483, AND CHARACTERIZATION OF VARIANT AH3 HIS-426.
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 [48]
RP VARIANT AH3 TRP-363.
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 [49]
RP VARIANTS AH3 LEU-30; ASN-172; LEU-281; LEU-283; TRP-356 AND SER-453.
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 [50]
RP VARIANTS HYPERANDROGENISM MET-304; SER-375 AND SER-453, AND
RP CHARACTERIZATION OF VARIANTS HYPERANDROGENISM MET-304; SER-375 AND SER-453.
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 [51]
RP VARIANTS AH3 CYS-408 AND SER-424.
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 [52]
RP VARIANTS AH3 THR-15; LEU-30; ASN-172; LEU-281 AND SER-453.
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 [53]
RP VARIANTS AH3 LEU-30; LEU-62; ASN-172; LEU-281; PRO-341; TRP-356; SER-453
RP AND PRO-483.
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 [54]
RP VARIANTS AH3 ASN-172; LEU-281; ARG-291; TYR-301; PRO-341; TRP-356 AND
RP GLN-483.
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 [55]
RP VARIANTS AH3 ASN-172; TRP-356 AND TRP-483.
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 [56]
RP VARIANT AH3 HIS-124.
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 [57]
RP VARIANTS AH3 THR-15; LEU-30; LEU-281 AND SER-482, AND CHARACTERIZATION OF
RP VARIANTS AH3 THR-15 AND SER-482.
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 [58]
RP VARIANTS AH3 LEU-30; ASN-172; ASN-236; GLU-237; LYS-239; LEU-281; SER-291;
RP GLN-356; TRP-356; TYR-365; SER-453; LEU-479 AND PRO-483, AND VARIANT
RP ARG-102.
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 [59]
RP VARIANTS AH3 LEU-30; ASN-172 AND TRP-356.
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 [60]
RP VARIANTS AH3 ARG-169; ARG-178; ARG-302 AND CYS-426, CHARACTERIZATION OF
RP VARIANTS AH3 ARG-169; ARG-178; ARG-302; CYS-426 AND HIS-426, 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 [61]
RP VARIANTS AH3 LEU-30; LEU-62; ASN-172; TRP-356 AND SER-453, AND
RP CHARACTERIZATION OF VARIANTS AH3 LEU-62 AND SER-453.
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 [62]
RP VARIANTS AH3 ARG-56; LEU-62; ARG-107; PRO-142; ASN-172; TRP-356; CYS-408
RP AND SER-453, AND CHARACTERIZATION OF VARIANTS AH3 ARG-56; LEU-62; ARG-107;
RP PRO-142; CYS-408 AND SER-453.
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 [63]
RP VARIANTS AH3 GLN-121 AND SER-453, AND CHARACTERIZATION OF VARIANT AH3
RP GLN-121.
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 [64]
RP VARIANTS AH3 THR-77; PRO-167; ASN-172; THR-230; LYS-233; LEU-281; SER-291;
RP ASP-292; LYS-320; PRO-341; HIS-354; TRP-356; TRP-369; CYS-408; SER-424;
RP HIS-426 AND SER-453, AND CHARACTERIZATION OF VARIANTS AH3 PRO-167; ASN-172;
RP LEU-281; ASP-292; LYS-320; TRP-369 AND SER-424.
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 [65]
RP VARIANT AH3 PHE-198.
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 [66]
RP VARIANTS AH3 HIS-191 AND ASN-282, CHARACTERIZATION OF VARIANTS AH3 HIS-191
RP AND ASN-282, 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 [67]
RP VARIANTS AH3 MET-12; PHE-113; 389-GLN--ALA-391 DEL AND PRO-450, VARIANTS
RP CYS-16; GLY-202; LEU-267 AND MET-450, CHARACTERIZATION OF VARIANTS AH3
RP MET-12; PHE-113; 389-GLN--ALA-391 DEL; PRO-450 AND SER-482,
RP CHARACTERIZATION OF VARIANTS CYS-16; GLY-202; LEU-267 AND MET-450,
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).
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 [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:50308, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:17252, ChEBI:CHEBI:28324,
CC ChEBI:CHEBI:57618, 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: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_046264, VSP_046265;
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: Seven non deleterious alleles are known: CYP21A2*1A,
CC CYP21A2*1B, CYP21A2*2, CYP21A2*3, CYP21A2*4, CYP21A2*5 and CYP21A2*6.
CC The sequence shown corresponds to allele CYP21A2*1B. Deleterious
CC alleles are mostly generated by recombinations between CYP21A2 and the
CC pseudogene CYP21A1P through gene conversion. This process consists of
CC recombination events that either delete CYP21A2 or transfer deleterious
CC mutations from CYP21A1P to CYP21A2.
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:3038528,
CC ECO:0000269|PubMed:3257825, ECO:0000269|PubMed:3260007,
CC ECO:0000269|PubMed:3267225, ECO:0000269|PubMed:3497399,
CC ECO:0000269|PubMed:3871526, ECO:0000269|PubMed:7749410,
CC ECO:0000269|PubMed:8478006, ECO:0000269|PubMed:8485582,
CC ECO:0000269|PubMed:8989258, ECO:0000269|PubMed:9067760,
CC ECO:0000269|PubMed:9187661, ECO:0000269|PubMed:9497336,
CC ECO:0000269|PubMed:9580109}. 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 -!- WEB RESOURCE: Name=PharmVar Pharmacogen Variation Consortium;
CC Note=CYP21A2 alleles;
CC URL="https://www.pharmvar.org/gene/CYP21A2";
CC ---------------------------------------------------------------------------
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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; GQ222286; ACT35412.1; -; Genomic_DNA.
DR EMBL; GQ222296; ACT35422.1; -; Genomic_DNA.
DR EMBL; GQ222301; ACT35427.1; -; Genomic_DNA.
DR EMBL; AK054616; BAB70774.1; -; mRNA.
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; CH471081; EAX03570.1; -; Genomic_DNA.
DR EMBL; CR936924; -; NOT_ANNOTATED_CDS; 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.
DR RefSeq; NP_001122062.3; NM_001128590.3.
DR PDB; 4Y8W; X-ray; 2.64 A; A/B/C=29-494.
DR PDBsum; 4Y8W; -.
DR AlphaFoldDB; P08686; -.
DR SMR; P08686; -.
DR BioGRID; 107961; 20.
DR IntAct; P08686; 2.
DR STRING; 9606.ENSP00000408860; -.
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; P08686; -.
DR PeptideAtlas; P08686; -.
DR PRIDE; P08686; -.
DR ProteomicsDB; 52155; -. [P08686-1]
DR ProteomicsDB; 63894; -.
DR Antibodypedia; 53182; 341 antibodies from 28 providers.
DR DNASU; 1589; -.
DR Ensembl; ENST00000383321.4; ENSP00000372811.4; ENSG00000206338.9.
DR Ensembl; ENST00000434026.2; ENSP00000392321.2; ENSG00000232414.6.
DR Ensembl; ENST00000435122.3; ENSP00000415043.2; ENSG00000231852.9.
DR Ensembl; ENST00000436607.6; ENSP00000403721.2; ENSG00000235134.7. [P08686-1]
DR Ensembl; ENST00000448314.6; ENSP00000398594.2; ENSG00000198457.13. [P08686-1]
DR Ensembl; ENST00000452386.2; ENSP00000403230.2; ENSG00000233151.6.
DR GeneID; 1589; -.
DR KEGG; hsa:1589; -.
DR UCSC; uc003nzf.3; human. [P08686-1]
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 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 InParanoid; P08686; -.
DR OrthoDB; 702827at2759; -.
DR PhylomeDB; P08686; -.
DR BioCyc; MetaCyc:HS09769-MON; -.
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 1061 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 90 other tissues.
DR ExpressionAtlas; P08686; baseline and differential.
DR Genevisible; P08686; HS.
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 Gene3D; 1.10.630.10; -; 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 Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
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..494
FT /note="Steroid 21-hydroxylase"
FT /id="PRO_0000051976"
FT BINDING 91
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /evidence="ECO:0000269|PubMed:25855791,
FT ECO:0007744|PDB:4Y8W"
FT BINDING 120
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /evidence="ECO:0000269|PubMed:25855791,
FT ECO:0007744|PDB:4Y8W"
FT BINDING 233
FT /ligand="17alpha-hydroxyprogesterone"
FT /ligand_id="ChEBI:CHEBI:17252"
FT /evidence="ECO:0000250|UniProtKB:P00191"
FT BINDING 233
FT /ligand="progesterone"
FT /ligand_id="ChEBI:CHEBI:17026"
FT /evidence="ECO:0000269|PubMed:25855791,
FT ECO:0007744|PDB:4Y8W"
FT BINDING 365
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /evidence="ECO:0000269|PubMed:25855791,
FT ECO:0007744|PDB:4Y8W"
FT BINDING 426
FT /ligand="heme b"
FT /ligand_id="ChEBI:CHEBI:60344"
FT /evidence="ECO:0000269|PubMed:25855791,
FT ECO:0007744|PDB:4Y8W"
FT BINDING 428
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 6
FT /note="L -> LL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046264"
FT VAR_SEQ 68..102
FT /note="VVVLNSKRTIEEAMVKKWADFAGRPEPLTYKLVSK -> KLVSR (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046265"
FT VARIANT 9
FT /note="L -> LL (in allele CYP21A2*2)"
FT /evidence="ECO:0000269|PubMed:1406709,
FT ECO:0000269|PubMed:2303461, ECO:0000269|PubMed:3038528,
FT ECO:0000269|PubMed:3267225"
FT /id="VAR_018363"
FT VARIANT 12
FT /note="L -> M (in AH3; non-classic form; unknown
FT pathological significance; no effect on steroid 21-
FT monooxygenase activity)"
FT /evidence="ECO:0000269|PubMed:27721825"
FT /id="VAR_077582"
FT VARIANT 15
FT /note="A -> T (in AH3; salt wasting form; unknown
FT pathological significance; no significant difference in
FT steroid 21-monooxygenase activity; dbSNP:rs63749090)"
FT /evidence="ECO:0000269|PubMed:12887291,
FT ECO:0000269|PubMed:15126570"
FT /id="VAR_026059"
FT VARIANT 16
FT /note="R -> C (decreased steroid 21-monooxygenase activity;
FT dbSNP:rs757608533)"
FT /evidence="ECO:0000269|PubMed:27721825"
FT /id="VAR_077583"
FT VARIANT 30
FT /note="P -> L (in AH3; non-classic form; 10% of non-classic
FT AH3 Texan patients; 50% steroid 21-monooxygenase activity;
FT 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 30
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 56
FT /note="G -> R (in AH3; loss of activity;
FT dbSNP:rs1413433421)"
FT /evidence="ECO:0000269|PubMed:18381579"
FT /id="VAR_065668"
FT VARIANT 62
FT /note="H -> L (in AH3; non-classic form; simple virilizing
FT form when associated with a second mild mutation such as S-
FT 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 64
FT /note="G -> E (in AH3; no activity)"
FT /evidence="ECO:0000269|PubMed:10408778"
FT /id="VAR_007923"
FT VARIANT 77
FT /note="I -> T (in AH3; simple virilizing form;
FT dbSNP:rs1333278223)"
FT /evidence="ECO:0000269|PubMed:20080860"
FT /id="VAR_065669"
FT VARIANT 90
FT /note="G -> V (in AH3)"
FT /evidence="ECO:0000269|PubMed:10364682"
FT /id="VAR_026061"
FT VARIANT 98
FT /note="K -> R (in dbSNP:rs1268071078)"
FT /id="VAR_001282"
FT VARIANT 102
FT /note="K -> R (in allele CYP21A2*3; dbSNP:rs6474)"
FT /evidence="ECO:0000269|PubMed:1406709,
FT ECO:0000269|PubMed:15110320, ECO:0000269|PubMed:3038528"
FT /id="VAR_001283"
FT VARIANT 105
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 107
FT /note="L -> R (in AH3; loss of activity;
FT dbSNP:rs957886272)"
FT /evidence="ECO:0000269|PubMed:18381579"
FT /id="VAR_065670"
FT VARIANT 113
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 121
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 124
FT /note="R -> H (in AH3; dbSNP:rs72552750)"
FT /evidence="ECO:0000269|PubMed:14676460"
FT /id="VAR_026062"
FT VARIANT 142
FT /note="L -> P (in AH3; loss of activity;
FT dbSNP:rs755020999)"
FT /evidence="ECO:0000269|PubMed:18381579"
FT /id="VAR_065672"
FT VARIANT 167
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 169
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 169
FT /note="C -> Y (in AH3)"
FT /evidence="ECO:0000269|PubMed:10094562"
FT /id="VAR_001285"
FT VARIANT 172
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 178
FT /note="G -> A (in AH3; dbSNP:rs72552751)"
FT /evidence="ECO:0000269|PubMed:10364682"
FT /id="VAR_026063"
FT VARIANT 178
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 183
FT /note="D -> E (in allele CYP21A2*4; dbSNP:rs397515531)"
FT /id="VAR_001287"
FT VARIANT 191
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 196
FT /note="Missing (in AH3; moderate)"
FT /evidence="ECO:0000269|PubMed:9497336"
FT /id="VAR_008688"
FT VARIANT 198
FT /note="L -> F (in AH3; dbSNP:rs143240527)"
FT /evidence="ECO:0000269|PubMed:21169732"
FT /id="VAR_075375"
FT VARIANT 202
FT /note="S -> G (decreased steroid 21-monooxygenase activity;
FT dbSNP:rs372964292)"
FT /evidence="ECO:0000269|PubMed:27721825"
FT /id="VAR_077585"
FT VARIANT 211
FT /note="V -> L (in AH3; non-classic form; pathogenicity
FT uncertain)"
FT /evidence="ECO:0000269|PubMed:3260007"
FT /id="VAR_026064"
FT VARIANT 230
FT /note="I -> T (in AH3)"
FT /evidence="ECO:0000269|PubMed:20080860"
FT /id="VAR_065674"
FT VARIANT 233
FT /note="R -> K (in AH3)"
FT /evidence="ECO:0000269|PubMed:20080860"
FT /id="VAR_065675"
FT VARIANT 236
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 237
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 239
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 261
FT /note="L -> P (in AH3; dbSNP:rs750337015)"
FT /evidence="ECO:0000269|PubMed:11598371"
FT /id="VAR_026065"
FT VARIANT 267
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 268
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 281
FT /note="V -> G (in AH3; salt wasting form)"
FT /evidence="ECO:0000269|PubMed:10720040"
FT /id="VAR_026066"
FT VARIANT 281
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 282
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 283
FT /note="M -> L (in AH3)"
FT /evidence="ECO:0000269|PubMed:12222711"
FT /id="VAR_026067"
FT VARIANT 291
FT /note="G -> C (in AH3)"
FT /evidence="ECO:0000269|PubMed:10364682"
FT /id="VAR_026068"
FT VARIANT 291
FT /note="G -> R (in AH3; dbSNP:rs201552310)"
FT /evidence="ECO:0000269|PubMed:12915679"
FT /id="VAR_018365"
FT VARIANT 291
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 292
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 300
FT /note="L -> F (in AH3; salt wasting form;
FT dbSNP:rs765001985)"
FT /evidence="ECO:0000269|PubMed:10720040"
FT /id="VAR_026069"
FT VARIANT 301
FT /note="S -> Y (in AH3)"
FT /evidence="ECO:0000269|PubMed:12915679"
FT /id="VAR_018366"
FT VARIANT 302
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 304
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 317
FT /note="L -> M (in AH3)"
FT /evidence="ECO:0000269|PubMed:11232002"
FT /id="VAR_026071"
FT VARIANT 320
FT /note="E -> K (in AH3; simple virilizing form; 4%
FT activity)"
FT /evidence="ECO:0000269|PubMed:20080860"
FT /id="VAR_065677"
FT VARIANT 339
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 341
FT /note="R -> P (in AH3; simple virilizing form;
FT dbSNP:rs747079101)"
FT /evidence="ECO:0000269|PubMed:12788866,
FT ECO:0000269|PubMed:12915679, ECO:0000269|PubMed:20080860"
FT /id="VAR_018367"
FT VARIANT 341
FT /note="R -> W (in AH3; non-classic form; mild;
FT dbSNP:rs72552755)"
FT /id="VAR_001295"
FT VARIANT 354
FT /note="R -> C (in AH3; salt wasting form;
FT dbSNP:rs772900496)"
FT /evidence="ECO:0000269|PubMed:10720040"
FT /id="VAR_026072"
FT VARIANT 354
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 356
FT /note="R -> P (in AH3; salt wasting form; 0.15% activity)"
FT /evidence="ECO:0000269|PubMed:9187661"
FT /id="VAR_001296"
FT VARIANT 356
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 356
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 362
FT /note="A -> V (in AH3; no activity)"
FT /evidence="ECO:0000269|PubMed:10408778"
FT /id="VAR_007924"
FT VARIANT 363
FT /note="L -> W (in AH3)"
FT /evidence="ECO:0000269|PubMed:11746135"
FT /id="VAR_026074"
FT VARIANT 365
FT /note="H -> Y (in AH3; dbSNP:rs1330554738)"
FT /evidence="ECO:0000269|PubMed:15110320"
FT /id="VAR_026075"
FT VARIANT 369
FT /note="R -> W (in AH3; dbSNP:rs781074931)"
FT /evidence="ECO:0000269|PubMed:20080860"
FT /id="VAR_065678"
FT VARIANT 375
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 380
FT /note="E -> D (in AH3; salt wasting form;
FT dbSNP:rs72552756)"
FT /evidence="ECO:0000269|PubMed:9067760"
FT /id="VAR_001299"
FT VARIANT 389..391
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 408
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 424
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 426
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 426
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 435
FT /note="R -> C (in AH3; dbSNP:rs767333157)"
FT /evidence="ECO:0000269|PubMed:11232002"
FT /id="VAR_026080"
FT VARIANT 450
FT /note="T -> M (decreased steroid 21-monooxygenase activity;
FT dbSNP:rs1319651744)"
FT /evidence="ECO:0000269|PubMed:27721825"
FT /id="VAR_077588"
FT VARIANT 450
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 453
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 479
FT /note="R -> L (in AH3; dbSNP:rs184649564)"
FT /evidence="ECO:0000269|PubMed:15110320"
FT /id="VAR_026081"
FT VARIANT 482
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 483
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 483
FT /note="R -> Q (in AH3; dbSNP:rs200005406)"
FT /evidence="ECO:0000269|PubMed:12915679"
FT /id="VAR_018368"
FT VARIANT 483
FT /note="R -> W (in AH3; salt wasting form;
FT dbSNP:rs759736443)"
FT /evidence="ECO:0000269|PubMed:14715874"
FT /id="VAR_026083"
FT VARIANT 493
FT /note="N -> S (in allele CYP21A2*6; dbSNP:rs6473)"
FT /evidence="ECO:0000269|PubMed:10391209,
FT ECO:0000269|PubMed:10496074, ECO:0000269|PubMed:1406709,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:3038528,
FT ECO:0000269|PubMed:7749410"
FT /id="VAR_001302"
FT MUTAGEN 268
FT /note="S->C,M,T: No loss of function."
FT /evidence="ECO:0000269|PubMed:1864962"
FT MUTAGEN 281
FT /note="V->I: Normal KM but 50% reduced Vmax."
FT MUTAGEN 281
FT /note="V->T: Normal KM but 10% reduced Vmax."
FT MUTAGEN 428
FT /note="C->M,S,T: Loss of activity and loss of P450
FT absorption."
FT /evidence="ECO:0000269|PubMed:1864962"
FT CONFLICT 155
FT /note="G -> D (in Ref. 7; BAB70774)"
FT /evidence="ECO:0000305"
FT CONFLICT 242
FT /note="R -> G (in Ref. 7; BAB70774)"
FT /evidence="ECO:0000305"
FT CONFLICT 277
FT /note="L -> Q (in Ref. 7; BAB70774)"
FT /evidence="ECO:0000305"
FT CONFLICT 304
FT /note="V -> A (in Ref. 7; BAB70774)"
FT /evidence="ECO:0000305"
FT CONFLICT 311
FT /note="P -> L (in Ref. 14; AAA59985)"
FT /evidence="ECO:0000305"
FT CONFLICT 346
FT /note="N -> I (in Ref. 14; AAA59985)"
FT /evidence="ECO:0000305"
FT CONFLICT 426
FT /note="R -> P (in Ref. 1; AAB59440)"
FT /evidence="ECO:0000305"
FT CONFLICT 437
FT /note="E -> D (in Ref. 1; AAB59440)"
FT /evidence="ECO:0000305"
FT HELIX 38..40
FT /evidence="ECO:0007829|PDB:4Y8W"
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 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 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 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 494 AA; 55887 MW; 7E1FF83B59FBA136 CRC64;
MLLLGLLLLP LLAGARLLWN WWKLRSLHLP PLAPGFLHLL QPDLPIYLLG LTQKFGPIYR
LHLGLQDVVV LNSKRTIEEA MVKKWADFAG RPEPLTYKLV SKNYPDLSLG DYSLLWKAHK
KLTRSALLLG IRDSMEPVVE QLTQEFCERM RAQPGTPVAI EEEFSLLTCS IICYLTFGDK
IKDDNLMPAY YKCIQEVLKT WSHWSIQIVD VIPFLRFFPN PGLRRLKQAI EKRDHIVEMQ
LRQHKESLVA GQWRDMMDYM LQGVAQPSME EGSGQLLEGH VHMAAVDLLI GGTETTANTL
SWAVVFLLHH PEIQQRLQEE LDHELGPGAS SSRVPYKDRA RLPLLNATIA EVLRLRPVVP
LALPHRTTRP SSISGYDIPE GTVIIPNLQG AHLDETVWER PHEFWPDRFL EPGKNSRALA
FGCGARVCLG EPLARLELFV VLTRLLQAFT LLPSGDALPS LQPLPHCSVI LKMQPFQVRL
QPRGMGAHSP GQNQ
