Disease relevance of Cyp21a1

• The sequence reported was assembled from the sequences of three overlapping lambda phage genomic clones from mouse strain B10.WR, which carries four tandem pairs of Slp and Cyp21 genes [1].
• Therefore, we analyzed the development, structure, and function of the adrenal medulla in 21-OH-deficient mice, an animal model resembling human congenital adrenal hyperplasia [2].
• Adrenal morphology of 21OH- mice showed lack of zonation, and hypertrophy and hyperplasia of adrenocortical mitochondria with few tubulovesicular christae [3].
• The feasibility of gene therapy for CAH was studied using 21OH-deficient mice (21OH-) and a replication-deficient adenovirus containing the genomic sequence of human CYP21 (hAdCYP21) [3].
• AAbs in patients with isolated autoimmune Addison's disease, autoimmune polyglandular syndromes types I and II, and 21-OH antibody-positive patients without overt Addison's disease (25 patients in total) were studied [4].

High impact information on Cyp21a1

• We found that there are two 21-OH genes in this region, located immediately 3' to the C4 and Slp genes [5].
• To determine whether 21-OH genes are located in the H-2 complex, we have now used a bovine adrenal complementary DNA clone encoding part of 21-OH to examine a cluster of overlapping cosmid clones derived from the S region of the BALB/c mouse [5].
• DNA fragments encoding the mouse steroid 21-hydroxylase (C21 or Cyp21A1) gene are de novo methylated when introduced into the mouse adrenocortical tumor cell line Y1 by DNA-mediated gene transfer [6].
• Lethal deletion of the complement component C4 and steroid 21-hydroxylase genes in the mouse H-2 class III region, caused by meiotic recombination [7].
• All data that were obtained supported the hypothesis that the meiotic, presumably unequal, recombination between homologous chromosomes of the H-2a and H-2wm7 haplotypes caused the deletion of the C4 and the 21-hydroxylase genes [7].

Chemical compound and disease context of Cyp21a1

• Collectively, results of these investigations suggest that esterification of 21-OH with various anhydrides did not improve receptor binding, inhibition of NO generation and ear edema inhibition, however, serum corticosterone level and local over systemic activities (L/S) were markedly improved [8].

Biological context of Cyp21a1

• We demonstrate that 21-OHD is caused by unequal crossing over between the active Cyp21a1 gene and the pseudogene resulting in a hybrid Cyp21a1-Cyp21a2-p gene including a partial deletion of Cyp21a1 [9].
• We report the sequence of a 26,307 bp long segment of the mouse genome that includes both the Slp and Cyp21 genes [1].
• Finally, some cells that are positive for Cyp21, which is normally expressed only in the adrenal gland, are found in the gonads of Wnt-4-deficient embryos, indicating that Wnt-4 may play a role in cell migration or in the sorting of adrenal and gonadal cells during early development [10].
• Nucleotide sequence analysis of murine 21-hydroxylase genes: mutations affecting gene expression [11].
• Comparison of the nucleotide sequences defines a deletion of 215 nucleotides spanning the second exon of the 21-OHase B gene; other nucleotide changes in the 21-OHase B gene introduce frame shifts and premature termination codons [11].

Anatomical context of Cyp21a1

• Deficiency of 21-hydroxylase (21-OH), one of the most common genetic defects in humans, causes low glucocorticoid and mineralocorticoid production by the adrenal cortex, but the effect of this disorder on the adrenomedullary system is unknown [2].
• 21-OH-deficient mice demonstrate severe adrenomedullary dysfunction, with alterations in chromaffin cell migration, development, structure, and catecholamine synthesis [2].
• Chromaffin cells of 21-OH-deficient mice exhibited ultrastructural features of neuronal transdifferentiation with reduced granules, increased rough endoplasmic reticulum and small neurite outgrowth [2].
• In this report we demonstrate that the mouse thymic epithelial cells (TEC) express the cytochrome P450 hydroxylases Cyp11A1, Cyp21, and Cyp11B1 [12].
• The cell lines secrete progesterone and 11-deoxycorticosterone, indicating these cells express the P450scc system, 3 beta-hydroxysteroid dehydrogenase, and 21-hydroxylase activity [13].

Associations of Cyp21a1 with chemical compounds

• Steroid 21-hydroxylase [21-OHase; steroid 21-monooxygenase; steroid, hydrogen-donor:oxygen oxidoreductase (21-hydroxylating); EC 1.14.99.10] is a cytochrome P-450 enzyme required for the adrenal synthesis of mineralocorticoids and glucocorticoids [11].
• The complete exon-intron structure of a human complement component C4A gene. DNA sequences, polymorphism, and linkage to the 21-hydroxylase gene [14].
• Prenatal dexamethasone treatment does not prevent alterations of the hypothalamic pituitary adrenal axis in steroid 21-hydroxylase deficient mice [15].
• The sequence of region D, CAAGGTCA, is very similar to the AAAGGTCA motif present in the mouse steroid 21-hydroxylase gene; the latter motif binds nerve-growth-factor-induced B factor (NGFI-B), which is a member of the thyroid/steroid/retinoid nuclear receptor gene family [16].
• Genes encoding 3 beta-hydroxysteroid dehydrogenase and steroid 21-hydroxylase P450c21, which catalyze the intermediate steps for syntheses of both aldosterone and corticosterone, were inducible in the three cell lines in temperature- and/or dibutyryl cAMP-dependent manners [17].

Physical interactions of Cyp21a1

• Specific mutations of NGFI-B shown previously to impair either DNA binding or transcriptional activation diminished the effect of NGFI-B coexpression on 21-OHase expression [18].

Regulatory relationships of Cyp21a1

• NGFI-B activates transcription through an NBRE of the gene encoding 21-hydroxylase (P450c21) in Y1 cells [19].

Other interactions of Cyp21a1

• Adrenocortical function and regulation of the steroid 21-hydroxylase gene in NGFI-B-deficient mice [19].
• Due to the lack of feedback inhibition by glucocorticoid, their circulating ACTH levels are exceedingly high; this results in ectopic Cyp21 gene expression in the testis [20].
• The gene encoding this protein is present in two copies (21-OHase A and B) in the S region of the murine major histocompatibility complex [11].
• As evidence that this cDNA encodes SF-1, we now show that it is selectively expressed in steroidogenic cells, that an antiserum against its protein product specifically abolishes the SF-1-related gel-shift complex, and that its coexpression increases promoter activity of the 21-hydroxylase 5'-flanking region in transfection experiments [21].
• The constitutive and cAMP-induced expression of the mouse steroid 21-hydroxylase gene (Cyp21) are impaired in adrenal cell mutants harboring mutations in cAMP-dependent protein kinase (cAMPdPK) [22].

Analytical, diagnostic and therapeutic context of Cyp21a1

• Southern blot analysis indicated that the aw18 haplotype has a deletion of the C4 gene and a deletion of one of the steroid 21-hydroxylase genes [7].
• This is the first demonstration that a single intra-adrenal injection of an adenoviral vector encoding CYP21 can compensate for the biochemical, endocrine and histological alterations in 21OH-deficient mice, and shows that gene therapy could be a feasible option for treatment of CAH [3].
• Survival of steroid 21-hydroxylase-deficient mice without endogenous corticosteroids after neonatal treatment and genetic rescue by transgenesis as a model system for treatment of congenital adrenal hyperplasia in humans [23].
• Expression of authentic 21-hydroxylase transcripts was quantitated by S1 nuclease protection assays using total RNA from pools of transfectant colonies [24].
• As determined by gel mobility shift assays with these elements, the dependence of the Cyp21 promoter elements on a functional cAMP-dependent protein kinase did not result from decreased expression or binding affinities of their respective DNA-binding proteins.(ABSTRACT TRUNCATED AT 250 WORDS)[22]

References