1.14.14.16 A15T natural mutation found in patients with classical congenital adrenal hyperplasia, no significant difference in activity compared to wild-type 659570 1.14.14.16 A265C naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 A265V naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 A265V the mutant enzyme activity is similar to wild type 698190 1.14.14.16 A391T naturally occuring mutation, the mutation disrupts the hydrophobicity of the region 728691 1.14.14.16 A434V naturally occuring mutation, the mutation causes steric clashes with the heme rendering the enzyme almost inactive 728691 1.14.14.16 C169R naturally occuring mutation, the mutation alters the region's hydrophobicity, conserved residue C169 makes hydrophobic interactions with the loop between E-F helices and F-helix 728691 1.14.14.16 D322G naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure 728691 1.14.14.16 D322G the mutation impacts significantly on enzyme function and exerts activity compatible with non-classical congenital adrenal hyperplasia, has about 27% activity for the conversion of progesterone to 11-deoxycorticosterone and 18% activity for the conversion of 17alpha-hydroxyprogesterone to 11-deoxycortisol compared to wild type activity 698190 1.14.14.16 D407N naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure 728691 1.14.14.16 E320K naturally occuring mutation, the mutation of E320, which is a highly conserved residue on a negatively charged Glu-Glu-Leu-Asp (EELD) motif, alters the charge on the motif 728691 1.14.14.16 E351K rare missense mutation located in the ERR triad and found in a patient with virilizing congenital hyperplasia. Residual activity is about 1% of wild-type for both 17-hydroxyprogesterone and progesterone 675489 1.14.14.16 E431K naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure 728691 1.14.14.16 F404S naturally occuring mutation, the mutation prevents stable packing interactions resulting in salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 G178A naturally occuring mutation, the mutation causes reduced structural flexibility of the sharp fold between the E- and F-helices 728691 1.14.14.16 G291C naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 G291R naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 G291S naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 G292C 0.32% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 G292D naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 G292S 0.0005% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 G424S naturally occuring mutation, the mutation imparts rigidity to the loop between K'- and L-helix 728691 1.14.14.16 G56R naturally occuring mutation, P57 and G56 form the hinge between the membrane interacting N-terminus and rest of the protein. The substitution of G56 with a polar and rigid Arg residue disrupts the hinge affecting the interactions of CYP21A2 with the membrane 728691 1.14.14.16 G65E 0.08% of wild-type activity with substrate progesterone 745776 1.14.14.16 G65E 0.082% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 G90V naturally occuring mutation, mutation of G90 to valine affects the ability of R91 to hydrogen bond with heme, causing salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 H119R naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 H365W the naturally occuring CYP21A2 mutant exhibits minimal 21-hydroxylase activity to convert 17-hydroxyprogesterone to 11-deoxycortisol or progesterone to 11-deoxycorticosterone compared to the wild-type 716052 1.14.14.16 H365Y naturally occuring mutation, the mutations causes the salt-wasting disease 728691 1.14.14.16 H365Y the naturally occuring CYP21A2 mutant exhibits minimal 21-hydroxylase activity to convert 17-hydroxyprogesterone to 11-deoxycortisol or progesterone to 11-deoxycorticosterone compared to the wild-type 716052 1.14.14.16 H365Y/R356W a naturally occuring 21-hydroxylase mutation in the CYP21A2 gene, that is involved in congenital adrenal hyperplasia, an autosomal recessive disorder, phenotype, overview. The H365Y enzyme is produced in more variable amounts than wild type 716052 1.14.14.16 H365Y/R356W heterozygote H365Y/R356W individuum for two CYP21A2 gene mutations each inherited from a different parent 716052 1.14.14.16 H62L naturally occuring mutation, the mutation may disrupt hydrogen bonding to reduce, but not eliminate, enzyme activity 728691 1.14.14.16 I171N mutation identified in Italian patient with congenital adrenal hyperplasia, less than 1% of wild-type enzyme activity 675491 1.14.14.16 I172N 0.006% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 I172N naturally occuring mutant, 0-2% of wild-type activity, dominant negative effect over wild-type with 11% decrease in activity 659781 1.14.14.16 I172N naturally occuring mutation, the mutation causes a loss of the hydrophobic pocket, I172 forms a hydrophobic pocket with M186 and M187 residues of F-helix 728691 1.14.14.16 I172N the mutation is associated with congenital adrenal hyperplasia 699034 1.14.14.16 I194N naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 I230T naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 I236N/V237E/M239K naturally occuring mutant, no enzymic activity, dominant negative effect over wild-type with 35% decrease in activity 659781 1.14.14.16 I471A site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme 726962 1.14.14.16 I471G site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme 726962 1.14.14.16 I77T naturally occuring mutation, the mutation disrupts the hydrophobic environment 728691 1.14.14.16 K121Q naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase 728691 1.14.14.16 K122Q missense mutation causing nonclassical 21-hydroxylase deficiency, shows reduced activity of 14% for the conversion of 17alpha-hydroxyprogesterone and 19% for the conversion of progesterone compared to wild type 699170 1.14.14.16 L107R naturally occuring mutation, the mutation abolishes heme binding and causes salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 L107X site-directed mutagenesis, inactive mutant 726962 1.14.14.16 L108R 0.0003% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 L109X site-directed mutagenesis, inactive mutant 726962 1.14.14.16 L142P naturally occuring mutation, the mutation of the D-helix causes helical disruption and destabilization of secondary structures 728691 1.14.14.16 L166P naturally occuring mutation, the mutation of the E-helix causes helical disruption and destabilization of secondary structures 728691 1.14.14.16 L167P naturally occuring mutation, the mutation of the E-helix causes helical disruption and destabilization of secondary structures 728691 1.14.14.16 L236N/V237E/M239K the mutation is associated with congenital adrenal hyperplasia 697794 1.14.14.16 L261P naturally occuring mutation, the mutation of the H-helix causes helical disruption and destabilization of secondary structures 728691 1.14.14.16 L300F naturally occuring mutation, the mutation causes localized destabilization of secondary structure 728691 1.14.14.16 L307M naturally occuring mutation, the mutation disrupts the optimal packing of side chains but does not alter the hydrophobic environment 728691 1.14.14.16 L307V naturally occuring mutation, the mutation disrupts the optimal packing of side chains but does not alter the hydrophobic environment 728691 1.14.14.16 L308F naturally occuring mutation, the mutation causes localized destabilization of secondary structure 728691 1.14.14.16 L353R naturally occuring mutation, the mutation abolishes heme binding and causes salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 L363W naturally occuring mutation, the mutation causes steric clashes with the heme rendering the enzyme almost inactive 728691 1.14.14.16 L446P mutation identified in Italian patient with congenital adrenal hyperplasia, less than 1% of wild-type enzyme activity 675491 1.14.14.16 L446P naturally occuring mutation, the mutation of the L-helix causes helical disruption and destabilization of secondary structures 728691 1.14.14.16 additional information an insertion (duplication) of 9-bp in exon 2 results in addition of three valine residues at codon 71 of the P450c21 protein lowering the structural stability of P450c21 thereby leading to the probable loss of its function 699034 1.14.14.16 additional information deletions/conversions involving the promoter region of the CYP21A2 gene (IVS2-12C/A>G, F306-L307insT) are associated with congenital adrenal hyperplasia 697794 1.14.14.16 additional information enzyme deficiency, i.e. 21-OHD, causes congenital adrenal hyperplasia, growth phenotypes of pubertal humans with salt wasting, simple virilizing, or non-classical 21-OHD, respectively, overview 688586 1.14.14.16 additional information replacement of N-terminal membrane anchor and basic regions by the basic regions of CYP2C3 for efficient expression and purification. N-terminal membrane anchor and sequence of the basic region do not significantly affect either substrate-specificity or 21-hydroxylase activites 671760 1.14.14.16 additional information two CYP21A2 intron 2 haplotype clusters, named c5 and c8, are related to the circulating steroid hormone levels in subjects with non-functioning adrenal incidentaloma 735122 1.14.14.16 N387K naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 P30E naturally occuring mutation causing disruption of the interaction between the carbon of P30 in the N-terminal loop and the side chain of Y376 within the beta5-beta6 hairpin loop resuting in the salt-wasting disease 728691 1.14.14.16 P30L missense mutation associated with congenital adrenal hyperplasia 696981 1.14.14.16 P30L the mutation is associated with congenital adrenal hyperplasia 697794 1.14.14.16 P31L 2.4% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 P31Q 0.0001% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 P432L naturally occuring mutation, the mutation makes the structure more flexible and prevents cysteine from being presented to heme 728691 1.14.14.16 P453S naturally occuring mutation, the mutation disrupts the hydrophobicity of the region 728691 1.14.14.16 P453S the mutant shows a reduced activity of 36% of wild type for the conversion of 17alpha-hydroxyprogesterone and 44% for the conversion of progesterone 699170 1.14.14.16 P459H naturally occuring mutation, the mutation disrupts the hydrophobicity of the region 728691 1.14.14.16 P463L naturally occuring mutation, the mutation interferes with the conformation of the beta8-beta9 loop with the subsequent closure of substrate entrance channel 728691 1.14.14.16 P482S natural mutation found in patients with nonclassical congenital adrenal hyperplasia, precocious pubarche, menstrual irregularities or hypertrichosis, about 70% of activity compared to wild-type 659570 1.14.14.16 Q318X the mutation is associated with congenital adrenal hyperplasia 697794 1.14.14.16 Q481P naturally occuring mutation, the mutation destabilizes the structure rendering the protein inactive 728691 1.14.14.16 R124H naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 R132C naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase 728691 1.14.14.16 R149C naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure 728691 1.14.14.16 R233G naturally occuring mutation, the mutation may prevent R233 from binding to the 3-keto oxygen of the proximal 17OHP in the proper orientation, it does not influence protein activity significantly, resulting in minimal phenotype 728691 1.14.14.16 R233K naturally occuring mutation, the mutation may prevent R233 from binding to the 3-keto oxygen of the proximal 17OHP in the proper orientation, it does not influence protein activity significantly, resulting in minimal phenotype 728691 1.14.14.16 R339H naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase 728691 1.14.14.16 R341P mutation identified in Italian patient with congenital adrenal hyperplasia, less than 1% of wild-type enzyme activity 675491 1.14.14.16 R341P naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase 728691 1.14.14.16 R341W naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase 728691 1.14.14.16 R356P naturally occuring mutation, the mutation disrupts the interaction of R356 with Q389 rendering the enzyme inactive and causing salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 R356W naturally occuring mutant, no enzymic activity, no dominant negative effect on wild-type 659781 1.14.14.16 R356W the mutation is associated with congenital adrenal hyperplasia 697794 1.14.14.16 R357W 0.01% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 R369Q naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase 728691 1.14.14.16 R408C/L naturally occuring mutation, the mutation destabilizes structural elements because of the extensive loss of hydrogen bonds 728691 1.14.14.16 R408H naturally occuring mutation, the mutation prevents normal hydrogen bonding with E351 and R354 728691 1.14.14.16 R409C 0.4% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 R426C naturally occuring mutation, the mutation disrupts the interaction of residues R91 and R426 rendering the protein nonfunctional and causing salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 R426H mutation identified in Italian patient with congenital adrenal hyperplasia, less than 1% of wild-type enzyme activity 675491 1.14.14.16 R435C naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure 728691 1.14.14.16 R479L naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure 728691 1.14.14.16 R483P naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure 728691 1.14.14.16 R483Q naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure 728691 1.14.14.16 R483Q the mutant enzyme activities in the conversion of progesterone to deoxycorticosterone and 17alpha-hydroxyprogesterone to 11-deoxycortisol are measured as 2.0 and 1.89% of the wild type, respectively 697429 1.14.14.16 S301Y naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 T168N naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 T241R site-directed mutagenesis, the mutant shows improved solubility properties compared to the wild-type enzyme 727898 1.14.14.16 T241R/L442A site-directed mutagenesis, the mutant shows greatly improved solubility properties compared to the wild-type enzyme 727898 1.14.14.16 T295X naturally occuring mutation, the mutation abolishes substrate binding and causes salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 T296N 0.05% of wild-type activity with substrate progesterone 745776 1.14.14.16 T296N 0.05% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 T450P naturally occuring mutation, the mutation reduces flexibility of beta8-sheet, which helps stabilize the very long C-terminal loop 728691 1.14.14.16 V139E naturally occuring mutation, mutation to glutamate disrupts the interaction with residues V440 and L436 on the L-helix causing instability of the enzyme, charge repulsions between the side chain of mutated V139E and E437 of the E-helix render the protein unstable and inactive causing salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 V249A naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 V281G naturally occuring mutation, the mutation causes a loss of the hydrophobic pocket 728691 1.14.14.16 V281L naturally occuring mutant, 50% of wild-type activity, dominant negative effect over wild-type with 30% decrease in activity 659781 1.14.14.16 V281L the mutation is associated with congenital adrenal hyperplasia 697794 1.14.14.16 V282L 2% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 V304M naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues 728691 1.14.14.16 V359A mutant displays significant 16alpha-hydroxylase activity. Substrate 16,17-dehydroprogesterone is converted to the 21-hydroxylated product and slightly more epoxide than wild-type 744331 1.14.14.16 V359A site-directed mutagenesis, the mutant shows 60% reduced activity compared to the wild-type enzyme 726962 1.14.14.16 V359A site-directed mutagenesis, the mutant shows altered product formation compared to the wild-type enzyme 726997 1.14.14.16 V359G site-directed mutagenesis, the mutant shows 10% reduced activity compared to the wild-type enzyme 726962 1.14.14.16 V470A site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme 726962 1.14.14.16 V470A/I471A site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme 726962 1.14.14.16 V470G site-directed mutagenesis, the mutant shows activity similar to the wild-type enzyme 726962 1.14.14.16 W302R naturally occuring mutation, the mutation prevents stable packing interactions resulting in salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 W302S naturally occuring mutation, the mutation prevents stable packing interactions resulting in salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 W302S the mutation impacts significantly on enzyme function and exerts activity compatible with simple virilizing congenital adrenal hyperplasia, has residual enzyme activity of about 3% compared to wild type activity for both, the conversion of progesterone to 11-deoxycorticosterone and the conversion of 17alpha-hydroxyprogesterone to 11-deoxycortisol 698190 1.14.14.16 W303R 0.0001% of wild-type efficiency with substrate progesterone 745363 1.14.14.16 Y47C naturally occuring mutation, the mutation disables hydrogen bonding with H38, the interaction is compensated by a weak His-Cys interaction 728691 1.14.14.16 Y47L naturally occuring mutation, the mutation disrupts hydrogen bonds and causes salt-wasting congenital adrenal hyperplasia 728691 1.14.14.16 Y59N naturally occuring mutation, the mutation disrupts the hydrophobicity of the region resulting in loss of function 728691