Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies were done to determine the effects of age on steroidogenesis in the inner (zona reticularis) and outer (zona fasciculata plus glomerulosa) zones of the guinea pig adrenal cortex. In 35-day-old animals, cortisol production by adrenal outer zone cells was approximately twice as great as that by inner zone cells. With aging, cortisol secretion by inner zone cells decreased to very low levels, but there was no detectable change in the capacity for cortisol production by the outer zone. However, the outer zone comprised a progressively decreasing fraction of the total adrenal mass in older animals. To determine the basis for the decline in cortisol production by inner zone cells with aging, the activities of several steroidogenic enzymes were determined. Microsomal 21-hydroxylase activity was greater in the inner than outer zone but was not significantly affected by age. By contrast, 17 alpha-hydroxylase activity was greater in the outer zone at all ages, and decreased with aging in the inner but not the outer zone. Mitochondrial cholesterol sidechain cleavage and 11 beta-hydroxylase activities were also higher in the outer than inner zone and declined in the inner zone only in older animals. The decrease in inner zone cholesterol sidechain cleavage activity with aging was proportionately greater than the age-dependent changes in other enzyme activities. The results indicate that the effects of aging on steroidogenesis are both zone- and enzyme-specific. The overall decline in cortisol secretion by the guinea pig adrenal cortex with aging is attributable to both a decrease in cortisol production by the cells of the zone reticularis and a disproportionate increase in the mass of the gland comprised by this zone. The decrease in cortisol secretion correlates closely with a decline in cholesterol sidechain cleavage activity in the zona reticularis, and may be causally related.
J Steroid Biochem Mol Biol 1993 Jun
PMID:Maturational changes in steroidogenesis in the inner and outer zones of the guinea pig adrenal cortex. 851 5

A method for genetic diagnosis of steroid 21-hydroxylase deficiency was developed based on allele-specific PCR. With this approach, genotyping of fourteen mutations and diagnosis of homozygous gene deletions can be performed within hours from tissue sampling. One patient with salt-wasting disease had normal genotype at all positions screened. DNA sequencing revealed two novel mutations, a G to C transversion at the conserved splice donor site of intron 7 and a TGG to TAG nonsense mutation at Trp 406 in exon 9. Allele-specific PCR was established also for these mutations and used to screen for their presence in the pseudogene. However, the two novel mutations were not found in at least 34 pseudogenes.
Hum Mol Genet 1993 May
PMID:Steroid 21-hydroxylase deficiency: two additional mutations in salt-wasting disease and rapid screening of disease-causing mutations. 851 86

The CYP21 gene that encodes the steroid 21-hydroxylase, P450c21, is overlapped on the opposite strand of DNA by the TX-X gene encoding the extracellular matrix protein, tenascin-X. These transcripts contain perfectly complementary segments of 299 bases at their 3'-ends. As these genes are tandemly duplicated and are transcribed in the adrenal cortex, we investigated whether these self-complementary transcripts formed RNA-RNA hybrids in vivo. Formation of heterogeneous nuclear ribonucleoprotein complexes between nascent RNA transcripts and nuclear proteins might modulate such potential RNA-RNA interactions. Using a double RNase protection assay, we found that these RNAs form very small amounts of double-stranded RNA-RNA hybrids in adrenal cells in vivo. To understand why these mRNAs fail to hybridize in vivo, we studied the actions of nuclear proteins on the binding and annealing of their complementary regions in vitro. The nucleation of interstrand annealing was kinetically favored over binding and was efficiently promoted by nuclear extracts. However, RNA-RNA strand zippering was inhibited, suggesting that protein binding and/or stable RNA secondary structures contribute to discontiguous base pairing. Increasing concentrations of nuclear proteins increased the relative proportion of these RNAs in perfect RNase-resistant duplexes but reached only about 20% of the total available RNA strands at saturating concentrations of nuclear proteins. Preincubation of either of the two single-stranded RNAs with nuclear proteins strongly inhibited the nucleation step of annealing, whereas preincubation of both strands abolished the annealing. RNase footprinting of the wild type and mutagenized overlapping transcripts suggested that sequence-specific binding of nuclear proteins is limited to the 5'-half of each RNA strand. These results indicate that the transcription of complementary, opposite-strand RNAs is not a mechanism for the regulation of the abundance of adrenal P450c21 mRNA and suggest that nuclear proteins strongly interfere with interstrand RNA base pairing in vitro as well as in vivo.
Mol Endocrinol 1995 Dec
PMID:Hybridization of the complementary mRNAs for P450c21 (steroid 21-hydroxylase) and tenascin-X is prevented by sequence-specific binding of nuclear proteins. 861 2

Certain differences in regional fat distribution might be explicable by subtle hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. We examined prospectively PA function relative to abdominal obesity defined by waist-to-hip circumference ratio (WHR) in 71 normotensive men aged 30-55 years. Basal PA activity was assessed by measurements of serum cortisol and plasma corticotropin (ACTH) concentrations during the oral glucose tolerance test (OGTT). Functional activity was examined by dexamethasone suppression and ACTH stimulation tests; responses of 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), cortisol, dehydroepiandrosterone (DHEA), and androstenedione were determined. When the subjects were divided into tertiles for the WHR, the ratio of mean ACTH to mean cortisol during the OGTT was increased (p < 0.05), and the ratio of urinary cortisol to body-mass index was decreased (p < 0.01), whilst the net increments of cortisol (p < 0.05) and 17-OHP (p < 0.05) from 0 to 60 min, as well as the ratio of 17-OHP to S increments (p < 0.05) after ACTH were elevated in the highest vs lowest WHR tertile. The ratio of mean ACTH to mean cortisol (r = 0.495; p < 0.001) during the OGTT, the ratio of net 17-OHP to S increments (r = 0.404; p < 0.001), and the net DHEA (r = 0.276; p = 0.020) and 17-OHP (r = 0.336; p = 0.005) responses to ACTH at 60 min correlated with WHR. In multivariate analyses the ratio of mean ACTH to cortisol, cortisol response to ACTH, and the ratio of net 17-OHP to S increments were all significant predictors of WHR independent of smoking, physical activity, and BMI explaining 49.0% of the variance in WHR. Thus, abdominal obesity may be associated with decreased activity of adrenal 21-hydroxylase. Either obesity-related functional alteration of 21-hydroxylase activity or the high carrier prevalence of genetic defects of this enzyme may explain these findings.
J Steroid Biochem Mol Biol 1996 Apr
PMID:Pituitary-adrenocortical function in abdominal obesity of males: evidence for decreased 21-hydroxylase activity. 880 94

Recently, we demonstrated that aldosterone is produced by human vascular cells, and that vascular aldosterone is linked to angiotensin II-induced hypertrophy of vascular smooth muscle cells. We therefore examined whether genes encoding steroidogenic enzymes responsible for aldosterone biosynthesis from cholesterol are expressed in vascular cells. Using polymerase chain reaction after reverse transcription, type I and II 3 beta-HSD (3 beta-hydroxysteroid dehydrogenase), P-450c21 (21-hydroxylase), and P-450c18 (18-hydroxylase/oxidase) genes were found to be expressed both in endothelial cells and smooth muscle cells cultivated from human pulmonary arteries. However, P-450scc (cholesterol side chain cleavage enzyme) and P-45011 beta (11 beta-hydroxylase) mRNAs could not be detected. These findings suggest that the enzyme system responsible for aldosterone production in human vascular cells is different from that found in the adrenal cortex and that vascular aldosterone may be synthesized from metabolic intermediates which originate from the circulation. Extra-adrenal 3 beta-HSD and steroid 21-hydroxylase occur in a wide variety of tissues. Thus, human vascular cells can retain the ability to produce aldosterone by expressing the P-450c18 gene.
Biochem Mol Biol Int 1996 Oct
PMID:The expression of steroidogenic enzyme genes in human vascular cells. 890 75

Tenascin-X (TN-X) is an extracellular matrix protein encoded by a large gene that overlaps the steroid 21-hydroxylase (P450c21) gene in the HLA locus on chromosome 6p21.3. This may be the most complex locus in the human genome identified to date, containing 13 overlapping transcription units in 160 kb of DNA. Previous studies determined the sequence of 39 TN-X exons, encoding a 12 kb open reading frame, but the promoter(s) of the gene had not been located. We identify the principal TN-X promoter and a previously unknown 5' untranslated exon that lies more than 10 kb upstream from the previously known exons. This promoter, which is substantially different from the promoter for TN-C, initiates transcription in human fetal adrenal and muscle, but expression in human NCI-H295 adrenocortical carcinoma cells is initiated by two other promoters lying further upstream. One of these is the same as the promoter for a recently identified Creb-related protein (Creb-rp), but transcripts initiated form this promoter in human adrenal NCI-H295 tumor cells are spliced differently from Creb-rp, and are largely retained in the nuclei of these cells. By analogy with the other two members of the tenascin family, TN-C and TN-R, it has been predicted that TN-X should undergo alternate splicing in its fibronectin-like domains. RACE cloning and RNase protection experiments reveal no such alternate splicing. The TN-X gene appears to be unique in having both its 5' and 3' ends buried in other genes.
Hum Mol Genet 1996 Nov
PMID:Alternate promoters and alternate splicing of human tenascin-X, a gene with 5' and 3' ends buried in other genes. 892 3

Steroid 21-hydroxylase deficiency is among the most common inborn errors of metabolism in man. Characterization of mutations in the 21-hydroxylase gene (CYP21) has permitted genetic diagnosis, facilitated by the polymerase chain reaction (PCR). The most common mutation is conversion of an A or C at nt656 to a G in the second intron causing aberrant splicing of mRNA. Homozygosity for nt656G is associated with profoundly deficient adrenal cortisol and aldosterone synthesis, secondary hypersecretion of adrenal androgens, and a severe form of congenital adrenal hyperplasia (CAH) characterized by ambiguous genitalia and/or sodium wasting in newborns. During the course of genetic analysis of CYP21 mutations in CAH families, we and others have noticed a number of relatives genotyped as nt656G homozygotes, yet showing no clinical signs of disease. A number of lines of evidence have led us to propose that the putative asymptomatic nt656G/G individuals are incorrectly typed due to dropout of one haplotype during PCR amplification of CYP21. For prenatal diagnosis, we recommend that microsatellite typing be used as a supplement to CYP21 genotyping in order to resolve ambiguities at nt656.
Hum Mol Genet 1996 Dec
PMID:Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees. 896 61

Steroid 21-hydroxylase encoded by CYP21 is expressed in adrenal cortex. Mutations in CYP21 cause potentially lethal congenital adrenal hyperplasia (CAH). Earlier observations suggested alternative sources of 21-hydroxylase activity, although its genetic source remains unclear. We found a novel source of CYP21 expression in normal human cultured B lymphocytes. The quantity of 21-hydroxylase transcript was reduced in B cell lines of CAH subjects compared with that in normal B-lymphoblastoid cells. No CYP21 transcript was detected in lymphocytes from a CAH patient with homozygous CYP21 deletion. Cultured lymphoid cells, including those carrying homozygous CYP21 deletion, and peripheral blood leukocytes converted both 17-hydroxyprogesterone to 11-deoxycortisol and progesterone to deoxycorticosterone. We conclude that lymphocytes express CYP21, but also possess a 21-hydroxylase distinct from CYP21. Activity of this isozyme may partially compensate for severe adrenal 21-hydroxylase deficiency.
Mol Cell Endocrinol 1997 Mar 14
PMID:Steroid 21-hydroxylase expression and activity in human lymphocytes. 909 96

Interest in extra-adrenal corticosteroid synthesis has been revived by technological advances and the quest for answers to clinical problems. The cytochrome P450 21-hydroxylase converts progesterone to deoxycorticosterone, the obligatory substrate for the production of the main adrenal steroids aldosterone, cortisol and corticosterone. The rat P450 21-hydroxylase was cloned and two constructs, 21OH-5 and 21OH-6, sequenced. The constructs are similar, except that 21OH-6 has three additional major insertions of 64, 70 and 84 bp, a 3 bp deletion, and four extra base pairs immediately before the poly-A sequence. The entire coding region of 21OH-5 has 87 and 71% homology with the mouse and human 21-hydroxylase cDNA, respectively, whereas the encoded protein has 84 and 65% homology. Reverse transcriptase-polymerase chain reaction (RT-PCR) combined with Southern blot demonstrated expression of both transcripts in the kidney, aorta, liver, cerebellum, hypothalamus and brain stem, heart and cerebrum, but not the hippocampus, in addition to the adrenal. The entire coding region of 21OH-5 and the corresponding region of 21OH-6 including the three introns were cloned into pCR3 and the plasmids transiently transfected into COS-7 cells. Only 21OH-5 was translated into active protein, converting approximately 64% of 3H-progesterone to deoxycorticosterone in 2 h.
J Steroid Biochem Mol Biol 1997 Jul
PMID:Cloning of two alternatively spliced 21-hydroxylase CDNAs from rat adrenal. 940 81

Premature adrenarche and functional adolescent androgen excess are common disorders which may evolve into polycystic ovary syndrome (PCOS). In all three disorders, ACTH-stimulated 17-hydroxyprogesterone concentrations are often somewhat elevated. To determine the role of 21-hydroxylase (CYP21) gene mutations in these disorders, we performed molecular genotype analysis on 48 children and adolescents referred for evaluation of hyperandrogenic findings and diagnosed as having premature adrenarche or functional androgen excess. For comparison, DNA samples from 80 healthy adults were genotyped. Seventeen of the 48 hyperandrogenic patients were found to be heterozygotic carriers of CYP21 mutations. The frequency of heterozygosity was significantly greater among symptomatic patients (35%) than among the healthy controls (6%), P < 0.001. Seven mutation-positive patients (50%) and only one mutation-negative patient had ACTH-stimulated 17-hydroxyprogesterone concentrations typical for heterozygotic carriers of 21-hydroxylase deficiency, 400-1000 ng/dl. The significant difference in heterozygote frequency between symptomatic patients and healthy controls suggests that heterozygosity for 21-hydroxylase deficiency may be associated with premature adrenarche and functional adolescent hyperandrogenism. Longitudinal studies are necessary to determine if heterozygosity for 21-hydroxylase deficiency predicts risk for PCOS.
Biochem Mol Med 1997 Dec
PMID:Hyperandrogenism and manifesting heterozygotes for 21-hydroxylase deficiency. 944 66


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