Disease relevance of CYP21A2

• Steroid 21-hydroxylase deficiency, the primary cause of congenital adrenal hyperplasia, is caused by defects of the CYP21A2 gene [1].
• This implies that approximately 1 in every 10 steroid 21-hydroxylase deficiency patients is a carrier of tenascin-X deficiency, which is associated with a recessive form of the Ehlers-Danlos syndrome [2].
• Each of these mutations was introduced into CYP21 cDNA which was then expressed in COS1 cells using a vaccinia virus system [3].
• Gene symbol: CYP21A2. Disease: adrenal hyperplasia, CYP21 [4].
• In search of a genetic linkage between the two immunodeficiencies, we examined the major histocompatibility complex (MHC) class III genes encoding complement components C2, C4A, and C4B and steroid 21-hydroxylase in addition to the HLA serotypes in individuals with either common variable immunodeficiency or IgA deficiency [5].

Psychiatry related information on CYP21A2

• These data raise the possibility of de novo cortisol biosynthesis during the first trimester of human development and are relevant to the pathophysiology of 46,XX virilization in CYP21 deficiency [6].

High impact information on CYP21A2

• We describe a new contiguous-gene syndrome, involving the CYP21B and TNX genes, that results in 21-hydroxylase deficiency and a connective-tissue disorder consisting of skin and joint hyperextensibility, vascular fragility and poor wound healing [7].
• DNA sequence analysis suggests that the mutation arose by a microconversion event involving exchange of up to 390 nucleotides between maternal CYP21A and CYP21B genes [8].
• Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a disorder of cortisol and aldosterone biosynthesis that results from mutations in the CYP21 gene encoding the adrenal 21-hydroxylase P-450c21 [9].
• We measured plasma and urinary levels of adrenal hormones, plasma renin activity, and sodium balance longitudinally in the patient and four other patients in whom adrenal hyperplasia had been diagnosed in infancy and in whom DNA analysis had predicted a complete absence of functional P-450c21 [9].
• Samples from eight patients with nonclassic 21-hydroxylase deficiency who had the haplotype HLA-B14,DR1 contained a hybridizing fragment 3700 base pairs long, indicating the presence of the valine-281 mutation in the CYP21B gene [10].

Chemical compound and disease context of CYP21A2

• Steroid 21-hydroxylase deficiency is the leading cause of impaired cortisol synthesis in congenital adrenal hyperplasia (CAH), with the nonclassic form (NC) comprising approximately 1% of the Caucasian population [11].
• Family studies of the steroid 21-hydroxylase and complement C4 genes define 11 haplotypes in classical congenital adrenal hyperplasia in The Netherlands [12].
• Steroid 21-hydroxylase (CYP21) deficiency is the major cause of congenital adrenal hyperplasia, a common genetic disease due to steroid imbalance [13].
• The HLA haplotype A3-Cw6-B47-C4A91-BQ0-DR7 is associated with congenital adrenal hyperplasia (CAH), since it only carries the dysfunctional steroid 21-hydroxylase A pseudogene as well as the 5' adjacent complement C4A gene [14].
• Three mutants (deletion of E196, G291S, and R483P) of steroid 21-hydroxylase (P450c21) from patients with inherited congenital adrenal hyperplasia had reduced activity toward progesterone and 17-hydroxyprogesterone after transient expression in cultured mammalian cells [15].

Biological context of CYP21A2

• Since it is unlikely that the term 'large-scale gene conversion' describes a mechanism that actually occurs between the CYP21A2 and CYP21A1P genes, we propose the discontinuation of that terminology [2].
• The main cause for the mutation of the CYP21A2 (c21B) gene is conversion of its nucleotide sequence to the neighboring homologous but nonfunctional c21A gene [13].
• Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21-hydroxylase deficiency: characteristics of three unusual haplotypes [1].
• Contemporary mutation-detection protocols based on the polymerase chain reaction often depend on the assumption that no more than one CYP21A2 gene is present on each chromosome 6 [1].
• The classical and nonclassical phenotypes of 21-hydroxylase deficiency represent a continuous spectrum of the impairment of 21-hydroxylase activity due to mutations between the CYP21A2 gene [16].

Anatomical context of CYP21A2

• Steroid 21-hydroxylase (P450c21) is a microsomal enzyme expressed in the adrenal gland that catalyzes conversion of 17-hydroxyprogesterone and progesterone to 11-deoxycortisol and deoxycorticosterone respectively [17].
• After transiently transfecting the plasmid constructs into mouse adrenocarcinoma Y1 cells, mouse testis Leydig tumor MA10 cells and human liver tumor HepG2 cells, our results showed that sequences located within the -13943/-13174 and -3278/-2586 regions upstream from the CYP21P had suppression effects on the promoter activity of human CYP21 [18].
• Congenital adrenal hyperplasia, caused by any one of a number of inborn errors of steroidogenesis in which cortisol is not sufficiently produced by the adrenal cortex, is in most cases due to a deficiency of the enzyme steroid 21-hydroxylase [19].
• Deletion mutants in the 5' upstream sequence of the human CYP21A2 gene demonstrated a novel regulatory DNA element responsible for cAMP-dependent expression of the gene in the transient expression system using Y-1 cells (mouse adrenocortical tumor cell line) [20].
• Meanwhile, 149 lipid-related genes were expressed in the gallbladder, 89 of which were first identified (with gray level in hybridization image), e.g. FASN (11.42+/-2.62), APOD (92.61+/-8.90) and CYP21A2 (246.11+/-42.36), and they were involved in each step of lipid metabolism pathway [21].

Associations of CYP21A2 with chemical compounds

• Blood cholesterol was grossly normal, and endocrine studies revealed defective CYP17A1 and CYP21A2 activities [22].
• RESULTS: In the PORD patients, pregnanediol, pregnanetriolone, and pregnanetriol were obviously elevated, and the urine steroid ratios reflecting CYP17A1 and CYP21A2 activities were decreased throughout the examined ages [23].
• Genetic analysis revealed that the girl was compound heterozygote for a previously reported Q318X mutation in exon 8 and a novel insertion of an adenine between nucleotides 962 and 963 in exon 4 of the CYP21A2 gene [24].
• CONCLUSIONS: We established a non-radioactive (biotin) Southern blot/hybridization methodology for CYP21A2 large rearrangements with good results [25].
• Our results show that there is a very high frequency (33%) of 21-hydroxylase deficiency haplotypes where functional CYP21B gene sequence has been removed as a consequence of CYP21 + C4 gene deletion while several haplotypes show evidence of gene addition [26].
• K121 is located on helix C in the CYP21 protein, which is part of the heme coordinating system [27].

Physical interactions of CYP21A2

• All eight chimeric CYP21 genes coupled with HLA-Bw47 in five unrelated patients had the CYP21A-CYP21B sequence transition within the same gene region (+1375 to +1993) [28].

Regulatory relationships of CYP21A2

• In most cases the CYP21-inactivating point mutations are transferred by apparent gene conversions from CYP21P to CYP21 [29].

Other interactions of CYP21A2

• Tenascin-X: a novel extracellular matrix protein encoded by the human XB gene overlapping P450c21B [30].
• Hybridization with specific oligonucleotide probes showed that in all 13 cases this remaining CYP21 gene carried an 8-base-pair deletion, typical of CYP21A, that prevents synthesis of a functional protein [31].
• DESIGN: Molecular analysis was performed by direct sequencing of PCR amplified products of the CYP21A2 and CYP11B1 genes [32].
• The remaining CRC's had deletions of C4 and/or CYP21 genes and were designated Bdel, Cdel and the like [33].
• Crude sediment extracts, containing high concentrations of polycyclic aromatic hydrocarbons (PAHs) and moderate amounts of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) significantly stimulated expression of the CYP11B2 gene (up to 10-fold induction), and suppressed expression of 3betaHSD2 and CYP21 genes [34].

Analytical, diagnostic and therapeutic context of CYP21A2

• This study used CYP21A2 genotyping (sequence/Southern blot analysis) to determine CAH carrier frequency in a middle European (Austrian) population [35].
• Sequence analysis of the complete functional CYP21A2 gene revealed three, not yet described mutations that represent a common pseudogene sequence [36].
• We performed simultaneous RFLP analyses of the CYP21 and C4 genes and determined the relative hybridization intensity of the genes using scanning densitometry of the X-ray films [37].
• RESULTS: After careful titration, we found that earlier failure to detect the chimeric CYP21P/CYP21 gene could be caused by unequal concentrations of two independent alleles as the PCR template or by the lack of primers to amplify chimeric molecules [38].
• Determination of deletion sizes in the MHC-linked complement C4 and steroid 21-hydroxylase genes by pulsed-field gel electrophoresis [39].

References