Affinage

CYP21A2

Steroid 21-hydroxylase · UniProt P08686

Length
495 aa
Mass
56.0 kDa
Annotated
2026-06-09
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYP21A2 encodes a microsomal cytochrome P450 enzyme of the adrenal cortex that catalyzes the 21-hydroxylation of progesterone to deoxycorticosterone and of 17-hydroxyprogesterone to 11-deoxycortisol, the committed step routing steroid precursors toward mineralocorticoid and glucocorticoid synthesis (PMID:8081391). Catalysis depends on a strict structural requirement of the substrate—a 3-oxo group at C-3 of ring A, which docking places in indispensable contact with the active-site residue Arg234, while other ring A configurations are tolerated (PMID:31404637). The enzyme operates as the terminal oxidase of a two-component system, drawing electrons from NADPH-dependent cytochrome P450 reductase (CPR) as its obligate redox partner, with catalytic output scaling directly with electron-transfer efficiency (PMID:26374204). Adrenal-restricted, cAMP-responsive transcription is driven through a unique promoter element (-126/-113 bp) bound by a purified 78 kDa adrenal-specific protein (ASP), which alone is sufficient to confer cAMP-inducible transcription and to enhance mRNA synthesis in vitro, with Sp1 occupying an overlapping adjacent site (PMID:1645728, PMID:1334085); transcription is further modulated by 1α,25-dihydroxyvitamin D3 through a promoter response element engaging VDR, WSTF, and VDIR comodulators (PMID:22561756). Loss-of-function mutations across the gene cause steroid 21-hydroxylase deficiency, and the degree of enzymatic compromise measured in expression assays correlates with clinical severity from salt-wasting through simple virilizing to nonclassical phenotypes (PMID:8081391, PMID:3257825); structure-function mapping attributes these effects to disruption of membrane anchoring, heme/substrate binding, protein stability, oxidoreductase interaction surfaces, or active-site integrity (PMID:23359706).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1988 High

    Established that a single coding missense change in CYP21 produces a stable but catalytically deficient enzyme, defining 21-hydroxylase deficiency as a loss-of-function disorder rather than a regulatory or expression defect.

    Evidence Site-directed mutagenesis of Ile-172→Asn expressed in transfected mouse Y1 adrenal cells with mRNA and activity analysis

    PMID:3257825

    Open questions at the time
    • Did not resolve which structural feature of the enzyme the residue maintains
    • Single mutation; spectrum of allelic effects not yet mapped
  2. 1990 High

    Identified the cis element responsible for adrenal-specific, cAMP-driven CYP21 expression, showing it is distinct from canonical CRE and bound by an adrenal-restricted nuclear factor.

    Evidence Chimeric reporter transfection, EMSA with adrenal vs. non-adrenal extracts, and cycloheximide inhibition

    PMID:2162843

    Open questions at the time
    • Binding factor not yet purified or identified
    • Relationship to general cAMP signaling machinery unresolved
  3. 1991 High

    Dissected the cAMP-responsive region into overlapping ASP and Sp1 binding sites and showed the ASP site alone suffices for cAMP induction, separating the adrenal-specific factor from the ubiquitous Sp1.

    Evidence EMSA, site-directed mutagenesis (G→C at -113/-112), and competition reporter assays, with bovine conservation

    PMID:1645728

    Open questions at the time
    • ASP identity remained unknown
    • Mechanistic link between cAMP signaling and ASP activity not defined
  4. 1992 High

    Purified the 78 kDa adrenal-specific protein ASP and demonstrated it directly drives transcription from the minimal CRE in a cell-free system, establishing it as the primary determinant of cAMP-dependent CYP21 regulation over Sp1.

    Evidence DNA-affinity purification, EMSA supershift, in vitro transcription, DNase I footprinting; parallel deletion analysis distinguishing CYP21 from CYP17 regulation

    PMID:1311271 PMID:1334085

    Open questions at the time
    • Gene encoding ASP not cloned
    • Signaling cascade coupling ACTH/cAMP to ASP function unresolved
  5. 1994 High

    Consolidated CYP21A2 as a microsomal adrenal P450 converting progesterone and 17-hydroxyprogesterone, and articulated the genotype-phenotype principle that residual enzymatic activity predicts disease severity.

    Evidence Review synthesizing transfection/expression and biochemical studies with cohort genotype-phenotype correlation

    PMID:8081391

    Open questions at the time
    • Structural basis of activity loss for individual mutations not yet defined
    • Redox partner requirement not directly demonstrated
  6. 1995 High

    Distinguished the two mutational mechanisms underlying CYP21 deficiency, showing large deletions arise in meiosis while gene conversions also occur mitotically.

    Evidence PCR detection of de novo events in matched sperm vs. leukocyte DNA from normal individuals with frequency estimation

    PMID:7479886

    Open questions at the time
    • Molecular determinants of recombination hotspots not defined
    • Does not address point mutation origins
  7. 1998 Medium

    Showed that a single promoter nucleotide distinguishing CYP21A2 from its pseudogene controls basal transcription and adrenal nuclear protein binding, linking pseudogene-derived microconversions to expression defects.

    Evidence Reporter assay, site-directed mutagenesis, and EMSA with adrenal extracts

    PMID:9518489

    Open questions at the time
    • Single lab
    • Identity of the bound nuclear protein not established
  8. 2002 Medium

    Demonstrated that mutations can impair catalysis without destabilizing the protein, defining a functional (active-site) versus structural (degradation) basis for milder versus severe phenotypes.

    Evidence In vitro activity assays with both substrates plus protein degradation analysis in COS-1 cells (V304M vs. G375S)

    PMID:12050257

    Open questions at the time
    • Single lab
    • Limited to two mutations
  9. 2008 Medium

    Mapped specific mutations to functional domains—membrane anchoring, the heme-coordinating system, and the P450 oxidoreductase interaction surface—and revealed synergistic activity loss when mild variants co-occur in cis.

    Evidence In vitro activity/kinetic assays in COS cells combined with homology-based 3D modeling (K121Q, H62L, P453S and others)

    PMID:18319307 PMID:18381579 PMID:18445671

    Open questions at the time
    • Modeling-based domain assignments not directly validated biochemically
    • Single-lab activity measurements
  10. 2012 High

    Identified vitamin D as a transcriptional modulator of CYP21A2, acting through a defined promoter response element and VDR/WSTF/VDIR comodulators whose balance can switch the effect between repressive and stimulatory.

    Evidence Reporter deletion constructs, ChIP, site-directed mutagenesis, and VDIR siRNA knockdown

    PMID:22561756

    Open questions at the time
    • Physiological significance of vitamin D regulation in vivo not established
    • Interplay with the cAMP/ASP axis unresolved
  11. 2013 Medium

    Provided a unifying structural framework correlating mutation location with phenotype, attributing salt-wasting, simple virilizing, and nonclassical disease to distinct classes of structural perturbation.

    Evidence Computational structure-function mapping of >100 mutations onto a humanized homology model from the bovine CYP21 crystal structure

    PMID:23359706

    Open questions at the time
    • No direct in vitro validation of newly classified mutations in this work
    • Predictions for individual variants require experimental confirmation
  12. 2018 High

    Defined the obligate redox dependency of CYP21A2 by reconstituting catalysis with CPR and showing that yield tracks electron-transfer efficiency, confirming CPR as the physiological electron donor.

    Evidence Whole-cell E. coli biotransformation with bicistronic CYP21A2/CPR co-expression and comparison of five redox systems

    PMID:26374204

    Open questions at the time
    • Performed with bovine enzyme and a synthetic substrate
    • Quantitative coupling parameters in native adrenal microsomes not measured
  13. 2019 High

    Defined the precise substrate determinant of catalysis—an obligatory C-3 oxo group engaging Arg234—explaining why progesterone and 17-hydroxyprogesterone are substrates while pregnenolone is not.

    Evidence In vitro activity assays with 16 synthetic steroid analogs plus endogenous steroids and molecular docking

    PMID:31404637

    Open questions at the time
    • Arg234 contact inferred from docking, not crystallography
    • Catalytic mechanism of hydroxyl transfer not directly resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity of the adrenal-specific transcription factor ASP and how ACTH/cAMP signaling is mechanistically transduced to activate it remain unresolved in the available corpus.
  • ASP gene not identified
  • Signaling pathway from cAMP to ASP activity undefined
  • No experimental crystal structure of human CYP21A2

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1430728 Metabolism 2
Partners
PORSP1VDIRVDRWSTF

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 A missense mutation in CYP21B (Ile-172→Asn, codon 172 ATC→AAC) causes steroid 21-hydroxylase deficiency; the mutant gene is expressed in transfected mouse Y1 adrenal cells and produces mRNA but an enzymatically deficient protein, establishing this as a loss-of-function coding mutation. Site-directed mutagenesis, transfection into mouse Y1 adrenal cells, mRNA expression analysis Proceedings of the National Academy of Sciences of the United States of America High 3257825
1990 A 34-nucleotide sequence (-129/-96 bp) in the 5'-flanking region of the human CYP21B gene is required for cAMP-dependent transcription; this element is distinct from the consensus CRE and binds a nuclear protein from adrenal (but not non-adrenal) cells in gel retardation assays, indicating an adrenal-specific transcription factor drives cAMP-dependent CYP21B expression. Chimeric reporter gene transfection assays (CAT, β-globin reporters), gel retardation/EMSA, cycloheximide inhibition experiments The Journal of biological chemistry High 2162843
1991 The cAMP-responsive element of CYP21B (-129/-96 bp) contains two overlapping protein-binding sites: one (-126/-113 bp) binds an adrenal-specific protein (ASP) and the other (-119/-110 bp) binds Sp1. The G→C substitution at -113/-112 bp abolishes binding of both ASP and Sp1 and eliminates cAMP-enhanced transcription. The -126/-113 bp ASP-binding sequence alone is sufficient to confer cAMP-inducible transcription and is functionally conserved in the bovine CYP21B gene. Gel shift assays (EMSA), site-directed mutagenesis, transient transfection reporter assays, competition analysis The Journal of biological chemistry High 1645728
1992 ASP, the adrenal-specific 78 kDa transcription factor binding the CYP21B cAMP-responsive element (-126/-113 bp), was purified by sequence-specific DNA-affinity chromatography. Antibody against ASP supershifts the DNA-ASP complex and inhibits in vitro transcription. Purified ASP enhances mRNA synthesis from the minimum CRE in a cell-free system, whereas Sp1 does not, establishing ASP as the primary transcription factor for cAMP-dependent CYP21B regulation. DNA-affinity chromatography purification, EMSA supershift, in vitro transcription assay, DNase I footprinting, SDS-PAGE The Journal of biological chemistry High 1334085
1992 The cAMP-responsive sequences (CRS) of CYP21B and CYP17 are distinct from each other and from known CRE consensus sequences; CYP21B CRS binds a putative adrenal-specific nuclear protein, while CYP17 CRSI binds a ubiquitous protein active only in steroidogenic cells, demonstrating that ACTH-dependent co-regulation of these two steroid hydroxylase genes operates through distinct biochemical mechanisms. Deletion analysis of upstream regulatory regions, nuclear protein binding assays FASEB journal Medium 1311271
1994 CYP21A2 (CYP21B) encodes a microsomal cytochrome P450 enzyme expressed in the adrenal gland that catalyzes conversion of 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to deoxycorticosterone; the degree of enzymatic compromise caused by each mutation is correlated with clinical severity of disease. Review synthesizing transfection/expression studies and biochemical characterization; genotype-phenotype correlation across patient cohorts Human mutation High 8081391
1995 De novo deletions of CYP21 (approximately 30 kb, breakpoints in intron 2/exon 3) are detected in sperm but not matched leukocyte DNA, occurring at frequencies of ~1/10^5–10^6 genomes, establishing they arise exclusively during meiosis. Gene conversions in the same region occur in both sperm and leukocyte DNA (~1/10^3–10^5 genomes), indicating gene conversions occur during mitosis (or both meiosis and mitosis), a distinct mechanism from unequal crossing-over. PCR detection of de novo events in matched sperm and leukocyte DNA from normal individuals Proceedings of the National Academy of Sciences of the United States of America High 7479886
1998 The -104G nucleotide in the CYP21 promoter (differing from the CYP21P pseudogene sequence) is required for basal transcription activity; changing -104G to the CYP21P sequence decreases basal transcription by ~80% in transfection assays and abolishes interaction with nuclear proteins from adrenal cells in gel-shift assays. Transient transfection reporter assay, site-directed mutagenesis, EMSA with adrenal nuclear extracts Nucleic acids research Medium 9518489
1999 Several novel CYP21 mutations (G90V, G291C, R354H, G178A) were functionally characterized by transient transfection in CHOP cells: G90V, G291C, and R354H effectively eliminated 21-hydroxylase activity toward both progesterone and 17α-hydroxyprogesterone, consistent with severe salt-wasting disease; G178A retained significant activity with 17α-hydroxyprogesterone, correlating with the milder simple virilizing phenotype. In vitro enzyme activity assay in transiently transfected CHOP cells with radiolabeled substrates (progesterone, 17α-hydroxyprogesterone) Biochemical and biophysical research communications Medium 10471376
2001 The IVS2+1G→A splice donor mutation in CYP21 causes generation of two aberrant transcripts when the genomic construct is transfected into COS-1 cells: one lacking exon 2 entirely, and one (~30% of transcripts) with inclusion of 3' intron 2 sequences due to use of a cryptic splice acceptor site, resulting in a non-functional protein. Transfection of CYP21 genomic construct into COS-1 cells, RT-PCR analysis of transcripts The Journal of endocrinology Medium 11739005
2002 The novel CYP21 missense mutation V304M shows 46% residual enzyme activity for 17-hydroxyprogesterone and 26% for progesterone conversion in COS-1 cells, with normal protein degradation, indicating a functional rather than structural defect consistent with nonclassical disease. G375S nearly abolishes enzyme activity (1.6% and 0.7% of normal for both substrates), consistent with classical disease. In vitro enzyme activity assay in transiently transfected COS-1 cells with both natural substrates; protein degradation analysis The Journal of clinical endocrinology and metabolism Medium 12050257
2006 Four novel CYP21 missense mutations (L166P, A391T, R479L, R483Q) were characterized by in vitro enzyme assay in transiently transfected mammalian cells; all showed reduced activity compared to wild-type for both natural substrates (17-hydroxyprogesterone and progesterone), spanning the full spectrum of disease severity from severe to mild. In vitro enzyme activity assay in transfected mammalian cells with radiolabeled 17-hydroxyprogesterone and progesterone Journal of molecular medicine Medium 17119906
2007 Microconversions between the CYP21A2 and CYP21A1P promoter regions (-126C>T, -113G>A, -110T>C) reduce CYP21A2 transcriptional activity to 52% of wild-type in luciferase reporter assays, contributing to the nonclassical CAH phenotype. EMSA demonstrated that the -132/-121 region is critical for interaction with the Sp1 transcription factor. Luciferase reporter transfection assays, EMSA with NCI-H295A nuclear extracts and wild-type/mutant probes, direct DNA sequencing The Journal of clinical endocrinology and metabolism Medium 17666484
2008 Three novel CYP21A2 mutations (p.G56R, p.L107R, p.L142P) and one recurrent mutation (p.R408C) were characterized by in vitro activity assay in transiently transfected COS-1 cells; all showed very low residual activity (<5% for both substrates), classifying them as classical CAH mutations. p.H62L showed activity within the nonclassical range; p.H62L+p.P453S in combination showed a synergistic reduction in activity greater than either alone. In vitro enzyme activity assay in transiently transfected COS-1 cells; apparent kinetic constants (Km) determined for H62L mutant The Journal of clinical endocrinology and metabolism Medium 18381579
2008 The novel CYP21A2 mutation K121Q (located on helix C) reduces 21-hydroxylase activity to ~14–19% of normal in transfected COS-7 cells. Protein modeling reveals K121 is in the heme-coordinating system and on the surface involved in P450 oxidoreductase interaction, suggesting the mutation impairs electron flux from P450 oxidoreductase to CYP21A2 and alters substrate affinity via heme dislocation. In vitro expression in transiently transfected COS-7 cells, homology-based 3D protein modeling The Journal of clinical endocrinology and metabolism Medium 18445671
2008 p.H62L alone reduces CYP21 enzyme activity similarly to the mild p.P453S mutation (nonclassical range); when p.H62L is combined with p.P453S on the same allele, enzymatic activity is synergistically reduced to a level intermediate between p.P453S and p.I172N. 3D modeling locates H62 in a domain involved in membrane anchoring. In vitro enzyme activity assay in transfected cells; 3D protein model analysis; phenotype correlation The Journal of clinical endocrinology and metabolism Medium 18319307
2012 1α,25-Dihydroxyvitamin D3 suppresses CYP21A2 transcription via a vitamin D receptor (VDR)-mediated mechanism. A vitamin D response element was identified in the CYP21A2 promoter; interaction of this element with VDR, WSTF, and VDIR comodulators was confirmed by chromatin immunoprecipitation. Deletion of this element abolished the vitamin D effect; siRNA knockdown of VDIR confirmed its involvement. An altered balance of comodulators can reverse the suppressive effect to stimulatory. Luciferase reporter assays with promoter deletion constructs, chromatin immunoprecipitation (ChIP), site-directed mutagenesis, siRNA knockdown Biochimica et biophysica acta High 22561756
2013 Using a humanized homology model of CYP21A2 based on the bovine crystal structure, CYP21A2 mutations causing complete loss of function (salt-wasting disease) affect membrane anchoring, heme/substrate binding, or protein stability; mutations causing simple virilizing disease alter the transmembrane region or conserved hydrophobic patches (up to 98% activity reduction); mild nonclassical disease results from interference with oxidoreductase interactions, salt-bridge/hydrogen-bonding networks, or nonconserved hydrophobic clusters. Computational structure-function modeling based on bovine CYP21 crystal structure; comprehensive mapping of >100 disease-causing mutations onto 3D model Proceedings of the National Academy of Sciences of the United States of America Medium 23359706
2015 A CYP21A2-based whole-cell biocatalytic system in E. coli (co-expressing bovine CYP21A2 with NADPH-dependent cytochrome P450 reductase, CPR, via a bicistronic vector) selectively 21-hydroxylates the synthetic substrate medrane to premedrol, demonstrating that CYP21A2 requires CPR as its redox partner for electron supply, and that the catalytic yield is directly dependent on the efficiency of the electron transfer system. Whole-cell biotransformation in E. coli; bicistronic co-expression of CYP21A2 and CPR; comparison of five alternative redox systems; bioreactor optimization Microbial cell factories High 26374204
2019 CYP21A2 requires a 3-oxo group at C-3 of the steroid substrate as a strict requirement for catalytic activity; all other ring A configurations tested (hydroxyl, oxo, fluoro, chloro groups; presence/absence of Δ1 and Δ4 double bonds; heteroatoms) were tolerated. Progesterone and 17-hydroxyprogesterone are hydroxylated at C-21, whereas (17-hydroxy-)pregnenolone (lacking the 3-oxo group) is not a substrate. Molecular docking suggests the C-3 carbonyl interacts indispensably with Arg234 in the active site. In vitro enzyme activity assay with sixteen synthetic 17,17-dimethyl-18-nor-13-ene steroid substrates plus endogenous steroids; molecular docking The Journal of steroid biochemistry and molecular biology High 31404637

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Tenascin-X: a novel extracellular matrix protein encoded by the human XB gene overlapping P450c21B. The Journal of cell biology 277 7686164
1988 Mutation in the CYP21B gene (Ile-172----Asn) causes steroid 21-hydroxylase deficiency. Proceedings of the National Academy of Sciences of the United States of America 226 3257825
1996 ACTH receptor, CYP11A1, CYP17 and CYP21A2 genes are expressed in skin. The Journal of clinical endocrinology and metabolism 186 8675607
2000 Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease. The Journal of experimental medicine 155 10859342
1999 Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations. The Journal of biological chemistry 148 10207042
1991 Distribution of deletions and seven point mutations on CYP21B genes in three clinical forms of steroid 21-hydroxylase deficiency. American journal of human genetics 148 1985465
2003 CYP21 gene mutation analysis in 198 patients with 21-hydroxylase deficiency in The Netherlands: six novel mutations and a specific cluster of four mutations. The Journal of clinical endocrinology and metabolism 139 12915679
1995 Gene conversions and unequal crossovers between CYP21 (steroid 21-hydroxylase gene) and CYP21P involve different mechanisms. Proceedings of the National Academy of Sciences of the United States of America 139 7479886
1994 Mutations in steroid 21-hydroxylase (CYP21). Human mutation 103 8081391
2013 Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. Proceedings of the National Academy of Sciences of the United States of America 95 23359706
1996 Direct molecular diagnosis of CYP21 mutations in congenital adrenal hyperplasia. Journal of medical genetics 91 8733045
2001 Partial purification and characterization of a hemolysin (CAH1) from Hawaiian box jellyfish (Carybdea alata) venom. Toxicon : official journal of the International Society on Toxinology 86 11223087
1999 Genotyping of CYP21, linked chromosome 6p markers, and a sex-specific gene in neonatal screening for congenital adrenal hyperplasia. The Journal of clinical endocrinology and metabolism 86 10084579
2017 CYP21A2 mutation update: Comprehensive analysis of databases and published genetic variants. Human mutation 80 29035424
1990 cAMP-dependent transcription of the human CYP21B (P-450C21) gene requires a cis-regulatory element distinct from the consensus cAMP-regulatory element. The Journal of biological chemistry 79 2162843
2018 Congenital Adrenal Hyperplasia (CAH) due to 21-Hydroxylase Deficiency: A Comprehensive Focus on 233 Pathogenic Variants of CYP21A2 Gene. Molecular diagnosis & therapy 75 29450859
2004 The novel Myb transcription factor LCR1 regulates the CO2-responsive gene Cah1, encoding a periplasmic carbonic anhydrase in Chlamydomonas reinhardtii. The Plant cell 74 15155888
1990 Direct analysis of CYP21B genes in 21-hydroxylase deficiency using polymerase chain reaction amplification. Molecular endocrinology (Baltimore, Md.) 74 2325662
1999 High incidence of molecular defects of the CYP21 gene in patients with premature adrenarche. The Journal of clinical endocrinology and metabolism 70 10323382
2003 CYP21 genotype, adult height, and pubertal development in 55 patients treated for 21-hydroxylase deficiency. The Journal of clinical endocrinology and metabolism 68 14671153
2002 Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex. American journal of human genetics 63 12226794
2017 The carbonic anhydrase CAH1 is an essential component of the carbon-concentrating mechanism in Nannochloropsis oceanica. Proceedings of the National Academy of Sciences of the United States of America 59 28396394
2001 The spectrum of molecular defects of the CYP21 gene in the Hellenic population: variable concordance between genotype and phenotype in the different forms of congenital adrenal hyperplasia. The Journal of clinical endocrinology and metabolism 57 11397897
2007 Microconversion between CYP21A2 and CYP21A1P promoter regions causes the nonclassical form of 21-hydroxylase deficiency. The Journal of clinical endocrinology and metabolism 55 17666484
2008 Inhibition of CYP21A2 enzyme activity caused by novel missense mutations identified in Brazilian and Scandinavian patients. The Journal of clinical endocrinology and metabolism 54 18381579
2002 Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes. Human genetics 53 12384784
1991 Evidence that an adrenal-specific nuclear protein regulates the cAMP responsiveness of the human CYP21B (P450C21) gene. The Journal of biological chemistry 51 1645728
2004 PCR-based detection of the CYP21 deletion and TNXA/TNXB hybrid in the RCCX module. Genomics 49 15081125
2001 CYP21 mutations and congenital adrenal hyperplasia. Clinical genetics 48 11359457
1999 Periplasmic carbonic anhydrase structural gene (Cah1) mutant in chlamydomonas reinhardtii. Plant physiology 48 10398710
2003 Dancing with complement C4 and the RP-C4-CYP21-TNX (RCCX) modules of the major histocompatibility complex. Progress in nucleic acid research and molecular biology 46 14604014
2002 Novel mutations in CYP21 detected in individuals with hyperandrogenism. The Journal of clinical endocrinology and metabolism 46 12050257
2006 Hyperandrogenism in carriers of CYP21 mutations: the role of genotype. Clinical endocrinology 43 16712666
1989 Two distinct areas of unequal crossingover within the steroid 21-hydroxylase genes produce absence of CYP21B. Genomics 43 2613228
2013 Comprehensive mutation analysis of the CYP21A2 gene: an efficient multistep approach to the molecular diagnosis of congenital adrenal hyperplasia. The Journal of molecular diagnostics : JMD 42 24071710
2000 The role of heterozygosity for CYP21 in the polycystic ovary syndrome. Journal of pediatric endocrinology & metabolism : JPEM 42 11117678
2003 Cis-acting elements and DNA-binding proteins involved in CO2-responsive transcriptional activation of Cah1 encoding a periplasmic carbonic anhydrase in Chlamydomonas reinhardtii. Plant physiology 40 14555782
1995 A promoter within intron 35 of the human C4A gene initiates abundant adrenal-specific transcription of a 1 kb RNA: location of a cryptic CYP21 promoter element? Human molecular genetics 40 8589688
2005 Prevalence of CYP21 mutations and IRS1 variant among women with polycystic ovary syndrome and adrenal androgen excess. Fertility and sterility 37 15705377
2017 Resveratrol inhibits androgen production of human adrenocortical H295R cells by lowering CYP17 and CYP21 expression and activities. PloS one 36 28323907
2011 Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche. European journal of endocrinology 35 21646284
2009 CYP21A2 gene mutations in congenital adrenal hyperplasia: genotype-phenotype correlation in Turkish children. Journal of clinical research in pediatric endocrinology 35 21274396
2004 The chimeric CYP21P/CYP21 gene and 21-hydroxylase deficiency. Journal of human genetics 35 14730433
1999 Mutation distribution and CYP21/C4 locus variability in Brazilian families with the classical form of the 21-hydroxylase deficiency. Acta paediatrica (Oslo, Norway : 1992) 35 10229037
1999 CO(2)-responsive transcriptional regulation of CAH1 encoding carbonic anhydrase is mediated by enhancer and silencer regions in Chlamydomonas reinhardtii. Plant physiology 34 10594120
1996 Circadian expression of the carbonic anhydrase gene, Cah1, in Chlamydomonas reinhardtii. Plant molecular biology 33 8980526
1992 Distinct biochemical mechanisms for cAMP-dependent transcription of CYP17 and CYP21. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 1311271
2003 Phenotype and genotype correlation of the microconversion from the CYP21A1P to the CYP21A2 gene in congenital adrenal hyperplasia. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 31 14502362
1998 Salt-wasting congenital adrenal hyperplasia: detection of mutations in CYP21B gene in a Chilean population. The Journal of clinical endocrinology and metabolism 31 9745454
1996 Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 31 8731325
1990 The swine steroid 21-hydroxylase gene (CYP21): cloning and mapping within the swine leucocyte antigen complex. Animal genetics 31 2109953
2008 p.H62L, a rare mutation of the CYP21 gene identified in two forms of 21-hydroxylase deficiency. The Journal of clinical endocrinology and metabolism 30 18319307
2004 Chimeric CYP21P/CYP21 and TNXA/TNXB genes in the RCCX module. Molecular genetics and metabolism 30 15639189
2002 Genetic analysis of Japanese patients with 21-hydroxylase deficiency: identification of a patient with a new mutation of a homozygous deletion of adenine at codon 246 and patients without demonstrable mutations within the structural gene for CYP21. The Journal of clinical endocrinology and metabolism 30 12050231
1992 Purification and characterization of a transcription factor which appears to regulate cAMP responsiveness of the human CYP21B gene. The Journal of biological chemistry 29 1334085
2015 Abundance of DLK1, differential expression of CYP11B1, CYP21A2 and MC2R, and lack of INSL3 distinguish testicular adrenal rest tumours from Leydig cell tumours. European journal of endocrinology 28 25609776
2011 Analysis of the CYP21A1P pseudogene: indication of mutational diversity and CYP21A2-like and duplicated CYP21A2 genes. Analytical biochemistry 27 21324303
2006 Characterization of novel missense mutations in CYP21 causing congenital adrenal hyperplasia. Journal of molecular medicine (Berlin, Germany) 27 17119906
2011 Mutation analysis of the CYP21A2 gene in the Iranian population. Genetic testing and molecular biomarkers 25 22017335
2000 Analysis of the chimeric CYP21P/CYP21 gene in steroid 21-hydroxylase deficiency. Clinical chemistry 25 10794740
2000 CYP21 and CYP21P variability in steroid 21-hydroxylase deficiency patients and in the general population in the Netherlands. European journal of human genetics : EJHG 25 11093272
2012 Molecular genetic analysis of CYP21A2 gene in patients with congenital adrenal hyperplasia. Indian journal of endocrinology and metabolism 24 22629504
1999 An unequal crossover between the RCCX modules of the human MHC leading to the presence of a CYP21B gene and a tenascin TNXB/TNXA-RP2 recombinant between C4A and C4B genes in a patient with juvenile rheumatoid arthritis. Experimental and clinical immunogenetics 24 10343159
2010 Molecular defects of the CYP21A2 gene in Greek-Cypriot patients with congenital adrenal hyperplasia. Hormone research in paediatrics 23 20838032
2002 Structural analysis of the chimeric CYP21P/CYP21 gene in steroid 21-hydroxylase deficiency. Journal of human genetics 22 12376740
2001 Molecular diagnosis of CYP21 mutations in congenital adrenal hyperplasia: implications for genetic counseling. American journal of pharmacogenomics : genomics-related research in drug development and clinical practice 22 12174671
2023 Long-read sequencing: An effective method for genetic analysis of CYP21A2 variation in congenital adrenal hyperplasia. Clinica chimica acta; international journal of clinical chemistry 20 37276943
2015 A CYP21A2 based whole-cell system in Escherichia coli for the biotechnological production of premedrol. Microbial cell factories 20 26374204
2004 Detection and assignment of CYP21 mutations using peptide mass signature genotyping. Molecular genetics and metabolism 20 15110320
1993 Organization and evolution of C4 and CYP21 genes in primates: importance of genomic segments. Immunogenetics 20 8093607
2011 Clinical phenotype and mutation spectrum of the CYP21A2 gene in patients with steroid 21-hydroxylase deficiency. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 19 22020670
1998 Mutations of the CYP21 gene in nonclassical steroid 21-hydroxylase deficiency in Japan. Endocrine journal 18 9881898
1998 Allele-dropout using PCR-based diagnosis for the splicing mutation in intron-2 of the CYP21B-gene: successful amplification with a Taq/Pwo-polymerase mixture. Endocrine research 18 9888552
2014 Molecular analysis of the CYP21A2 gene in Chinese patients with steroid 21-hydroxylase deficiency. Clinical biochemistry 17 24503005
2005 Molecular analysis of the CYP21 gene and prenatal diagnosis in families with 21-hydroxylase deficiency in northeastern Iran. Hormone research 17 15775714
2020 Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: An Update on Genetic Analysis of CYP21A2 Gene. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 16 32131114
2014 Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations. Indian journal of endocrinology and metabolism 16 25538881
2012 Vitamin D-mediated regulation of CYP21A2 transcription - a novel mechanism for vitamin D action. Biochimica et biophysica acta 16 22561756
2003 Mutation of IVS2 -12A/C>G in combination with 707-714delGAGACTAC in the CYP21 gene is caused by deletion of the C4-CYP21 repeat module with steroid 21-hydroxylase deficiency. The Journal of clinical endocrinology and metabolism 16 12788880
2019 Fine-mapping of the substrate specificity of human steroid 21-hydroxylase (CYP21A2). The Journal of steroid biochemistry and molecular biology 15 31404637
2015 Molecular genetic study of congenital adrenal hyperplasia in Serbia: novel p.Leu129Pro and p.Ser165Pro CYP21A2 gene mutations. Journal of endocrinological investigation 15 26233337
2014 Mutational analysis of CYP21A2 gene and CYP21A1P pseudogene: long-range PCR on genomic DNA. Methods in molecular biology (Clifton, N.J.) 15 24823785
2007 Three novel CYP21A2 mutations and their protein modelling in patients with classical 21-hydroxylase deficiency from northeastern Iran. Clinical endocrinology 15 17573904
2005 Diversity of the CYP21P-like gene in CYP21 deficiency. DNA and cell biology 15 15684714
2001 Multiple transcripts of the CYP21 gene are generated by the mutation of the splicing donor site in intron 2 from GT to AT in 21-hydroxylase deficiency. The Journal of endocrinology 15 11739005
1992 CYP21/C4 gene organisation in Italian 21-hydroxylase deficiency families. Human genetics 15 1551657
1991 Extended MHC haplotypes and CYP21/C4 gene organisation in Irish 21-hydroxylase deficiency families. Human genetics 15 1677925
2017 Variations in the 3'UTR of the CYP21A2 Gene in Heterozygous Females with Hyperandrogenaemia. International journal of endocrinology 14 28487735
1999 Functional analysis of four CYP21 mutations from spanish patients with congenital adrenal hyperplasia. Biochemical and biophysical research communications 14 10471376
1998 The -104G nucleotide of the human CYP21 gene is important for CYP21 transcription activity and protein interaction. Nucleic acids research 14 9518489
1997 Characterisation of CAH alleles with non-radioactive DNA single strand conformation polymorphism analysis of the CYP21 gene. Journal of medical genetics 14 9132494
1990 Exon 7 Ncol restriction site within CYP21B (steroid 21-hydroxylase) is a normal polymorphism. Molecular endocrinology (Baltimore, Md.) 14 1978247
2022 Long-read Amplicon Sequencing of the CYP21A2 in 48 Thai Patients With Steroid 21-Hydroxylase Deficiency. The Journal of clinical endocrinology and metabolism 13 35363313
2019 Carriers of a Classic CYP21A2 Mutation Have Reduced Mortality: A Population-Based National Cohort Study. The Journal of clinical endocrinology and metabolism 13 31393570
2012 Investigation of CYP21A2 mutations in Turkish patients with 21-hydroxylase deficiency and a novel founder mutation. Gene 13 23142378
2010 Identification of CYP21A2 mutant alleles in Czech patients with 21-hydroxylase deficiency. International journal of molecular medicine 13 20818501
2008 Functional and structural consequences of a novel point mutation in the CYP21A2 gene causing congenital adrenal hyperplasia: potential relevance of helix C for P450 oxidoreductase-21-hydroxylase interaction. The Journal of clinical endocrinology and metabolism 13 18445671
2005 Structural and functional analysis of a novel mutation of CYP21B in a heterozygote carrier of 21-hydroxylase deficiency. Human genetics 13 16028060
1992 Comparison of cAMP-responsive DNA sequences and their binding proteins associated with expression of the bovine CYP17 and CYP11A and human CYP21B genes. The Journal of steroid biochemistry and molecular biology 13 22217838
2017 CYP21A2 intronic variants causing 21-hydroxylase deficiency. Metabolism: clinical and experimental 12 28521877

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