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Congenital adrenal hyperplasia is a disorder occurring in both sexes and is the commonest cause of ambiguous genitalia. It is a group of autosomal recessive disorders in which, on the basis of an enzyme defect the bulk of steroid hormone production by adrenal cortex shifts from corticosteroids to androgens. Autosomal recessive mutations in the CYP21, CYP17, CYP11B1 and 3betaHSD genes that encode steroidogenic enzymes, in addition to mutations in the gene encoding the intracellular cholesterol transport protein steroidogenic acute regulatory protein StAR can cause CAH. Each of the defects causes different biochemical consequences and clinical features. Deficiencies in 21 hydroxylase (21-OH) and 11beta-Hydroxylase (11beta-OH) are the two most frequent causes of CAH. All the biochemical defects impair cortisol secretion, resulting into compensatory hypersecretion of ACTH and consequent hyperplasia of the adrenal cortex. Research in recent years has clarified clinical, biochemical and genetic problems in diagnosis and treatment of the disorders. Expanding knowledge of the gene mutations associated with each of these disorders is providing valuable diagnostic tools in addition to the biochemical profile and phenotype. Genotyping is useful in selecting instances to provide genetic counseling and to clarify ambiguous cases.  相似文献   

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Twelve of 24 monospecific caprine reagents produced by absorption of alloimmune antisera identified a complex blood group system of goats which was designated B, based on the results of a small comparison test with ovine reagents. The frequencies of the 12 B factors differed significantly among the Australian Angora, Texan Angora, Cashmere, and Dairy goat breeds. Three of the antigens detected by the reagents were shown to be related as linear subtypes, designated Ba1, Ba2, and Ba3, and inherited as alleles. The segregations of B factors in 80 sire groups involving 1086 offspring demonstrated that groups of B factors (phenogroups) segregated as products of allelic genes. This work was supported by a grant from the Australian Stud Book, Alison Road, Randwick, New South Wales 2031, Australia.  相似文献   

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The Wnt family molecules Dickkopf-3 (DKK3) and WNT4 are present at higher concentrations in the zona glomerulosa than in the rest of the adrenal cortex. In order to study direct effects of these proteins on adrenocortical cell function, we created adenoviruses encoding human DKK3 and WNT4. When added to cultured human adrenocortical cells, DKK3 inhibited aldosterone and cortisol biosynthesis, either alone or together with cyclic AMP. WNT4 increased steroidogenesis when added alone but decreased it in the presence of cyclic AMP. A control adenovirus encoding GFP had no effect. RNA was prepared from cultured cells and was assayed by real-time PCR. CYP11A1 (cholesterol side-chain cleavage enzyme), HSD3B2 (3beta-hydroxysteroid dehydrogenase type II), CYP17 (17alpha-hydroxylase), CYP21 (21-hydroxylase) and CYP11B1 (11beta-hydroxylase) mRNAs were all increased by cyclic AMP, whereas CYP11B2 (aldosterone synthase) was unaffected. DKK3 decreased cyclic AMP-stimulated CYP17. WNT4 increased both CYP17 and CYP21 in the absence of cyclic AMP. Both DKK3 and WNT4 increased the level of CYP11B2. These data show that these Wnt signaling molecules have multiple actions on steroidogenesis in adrenocortical cells, including effects on overall steroidogenesis (aldosterone and cortisol biosynthesis) and distinct effects on steroidogenic enzyme mRNA levels. The co-localization of DKK3 and WNT4 in the glomerulosa and their stimulation of CYP11B2 imply an action on glomerulosa-specific function.  相似文献   

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It is not clear if an increase in intra-adrenal cortisol is required to mediate the actions of adrenocorticotropic hormone (ACTH) on adrenal growth and steroidogenesis during the prepartum stimulation of the fetal pituitary-adrenal axis. We infused metyrapone, a competitive inhibitor of cortisol biosynthesis, into fetal sheep between 125 and 140 days of gestation (term = 147 +/- 3 days) and measured fetal plasma cortisol, 11-desoxycortisol, and ACTH; pituitary pro-opiomelanocortin mRNA and adrenal expression of ACTH receptor (melanocortin type 2 receptor), steroidogenic acute regulatory protein (StAR), 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), cytochrome P450 17-hydroxylase (CYP17), 3beta-hydroxysteroid dehydrogenase, and cytochrome P450 21-hydroxylase mRNA; and StAR protein in the fetal adrenal gland. Plasma ACTH and 11-desoxycortisol concentrations were higher (P < 0.05), whereas plasma cortisol concentrations were not significantly different in metyrapone- compared with vehicle-infused fetuses. The ratio of plasma cortisol to ACTH concentrations was higher (P < 0.0001) between 136 and 140 days than between 120 and 135 days of gestation in both metyrapone- and vehicle-infused fetuses. The combined adrenal weight and adrenocortical thickness were greater (P < 0.001), and cell density was lower (P < 0.01), in the zona fasciculata of adrenals from the metyrapone-infused group. Adrenal StAR mRNA expression was lower (P < 0.05), whereas the levels of mature StAR protein (30 kDa) were higher (P < 0.05), in the metyrapone-infused fetuses. In addition, adrenal mRNA expression of 11betaHSD2, CYP11A1, and CYP17 were higher (P < 0.05) in the metyrapone-infused fetuses. Thus, metyrapone administration may represent a unique model that allows the investigation of dissociation of the relative actions of ACTH and cortisol on fetal adrenal steroidogenesis and growth during late gestation.  相似文献   

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Subdivision of TF B into two variants, B1 (faster) and B2 (slower) in Australian goat breeds was accomplished by high voltage, thin layer polyacrylamide gel electrophoresis at pH 7.9. The genes controlling the caprine transferrins were shown to be autosomal codominant alleles, TFA, TFB1, TFB2 and TFC and in the various breeds of goats, the alleles were in Hardy-Weinberg equilibrium. TFA was the most common allele in the Australian and Texan Angora, Cashmere and Dairy breeds with gene frequencies ranging from 0.652 to 0.977. TFB1 and TFB2 occurred in all four breeds while TFC was only observed in very low frequencies in Australian Angora and Cashmere breeds.  相似文献   

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The steroid 17-hydroxylase cytochrome P450 (CYP17) found in mammalian adrenal and gonadal tissues typically exhibits not only steroid 17-hydroxylase activity but also C-17,20-lyase activity. These two reactions, catalyzed by CYP17, allow for the biosynthesis of the glucocorticoids in the adrenal cortex, as a result of the 17-hydroxylase activity, and for the biosynthesis of androgenic C(19) steroids in the adrenal cortex and gonads as a result of the additional lyase activity. A major difference between species with regard to adrenal steroidogenesis resides in the lyase activity of CYP17 toward the hydroxylated intermediates and in the fact that the secretion of C(19) steroids takes place, in some species, exclusively in the gonads. Ovine CYP17 expressed in HEK 293 cells converts progesterone to 17-hydroxyprogesterone and pregnenolone to dehydroepiandrosterone via 17-hydroxypregnenolone. In ovine adrenal microsomes, minimal if any lyase activity was observed toward either progesterone or pregnenolone. Others have demonstrated the involvement of cytochrome b(5) in the augmentation of CYP17 lyase activity. Although the presence of cytochrome b(5) in ovine adrenocortical microsomes was established, ovine adrenal microsomes did not convert pregnenolone or 17-hydroxypregnenolone to dehydroepiandrosterone. Furthermore the addition of purified ovine cytochrome b(5) to ovine adrenal microsomes did not promote lyase activity. We conclude that, in the ovine adrenal cortex, factors other than cytochrome b(5) influence the lyase activity of ovine CYP17.  相似文献   

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Inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) regulate the activity of the hypothalamo-pituitary-adrenal (HPA) axis at several levels. Although hypothalamic CRH secretion may be the primary mechanism by which these cytokines activate the HPA axis, IL-1 expression is increased within the adrenal glands in models for systemic inflammation, and IL-1 may augment adrenal glucocorticoid production. Our aim was to investigate the direct effects of IL-1α and IL-1β on adrenal steroidogenesis and expression of three key steroidogenic genes in human adrenocortical cells using the NCI-H295R cell line as a model. mRNAs encoding receptors for IL-1, TNF-α, and leukemia inhibitory factor (LIF) were detectable in the cell line (Affymetrix microarray analysis). Both IL-1α and IL-1β increased cortisol, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate production, and the accumulation of mRNAs for steroidogenic acute regulatory protein (STAR), 17α-hydroxylase/17,20-lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase 2 (HSD3B2) in these cells (P<0.05 for all). Both ILs augmented TNF-α- and LIF-induced STAR and CYP17A1 mRNA accumulation, and TNF-α-induced cortisol production (P<0.05 for all). Both ILs also increased the apoptotic index of the cells (P<0.05), which was efficiently neutralized by their specific antibodies. The IL-induced changes in the STAR, HSD3B2, and CYP17A1 protein levels were not as evident as those in the respective mRNA levels. In conclusion, the combined effect of inflammatory cytokines at the adrenal level in acute or chronic inflammatory states could significantly stimulate glucocorticoid production, and thus explain the observed discrepancy between the cortisol and ACTH concentrations sometimes seen in sepsis and chronic inflammatory states.  相似文献   

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OBJECTIVES: Ethnic differences in prostate cancer incidence are well documented, with African-Americans having among the highest rates in the world. Ethnic differences in genotypes for genes associated with androgen metabolism including SRD5A2 and CYP3A4 also may exist. The aim of this study was to evaluate differences in these genotypes by ethnicity. METHODS: We studied cancer-free controls representative of four groups: 147 African Americans, 410 Caucasian-Americans, 129 Ghanaians, and 178 Senegalese. PCR-based genotype analysis was undertaken to identify two alleles (V89L, A49T) at SRD5A2 and *1B allele at CYP3A4. RESULTS: Differences were observed for V89L (variant frequency of 30% in Caucasians, 27% in African Americans, 19% in Ghanaians, and 18% in Senegalese, p = 0.002) and were observed for CYP3A4*1B (variant frequencies of 8% in Caucasians, 59% in African Americans, 81% in Ghanaians, and 78% in Senegalese, p = 0.0001). Pooled data combining the present data and previously published data from from Asian, Hispanic, and Arab cancer-free controls showed significant ethnic differences for SRD5A2 and CYP3A4 polymorphisms. Overall, Asians were least likely to have alleles associated with increased prostate cancer risk, while Africans were most likely to have those alleles. CONCLUSIONS: These results suggest that ethnicity-specific differences in genotype frequencies exist for SRD5A2 and CYP3A4. Africans and African-Americans have the highest frequency of those alleles that have previously been associated with increased prostate cancer risk. Future studies should address whether allele frequency differences in part explain differences in prostate cancer incidence in these populations.  相似文献   

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张宁宁  王长楠  倪鑫 《生理学报》2020,72(2):148-156
肾上腺是人体重要的内分泌器官。由于缺乏肾上腺皮质束状带特异性表达Cre酶的工具鼠,目前对肾上腺皮质束状带细胞中特异表达基因的功能缺乏深入的解析。CYP11B1基因编码类固醇11β-羟化酶,该酶是糖皮质激素合成的关键酶,在肾上腺皮质束状带中特异性表达。本研究旨在利用CYP11B1基因在束状带特异性表达的特点,构建在肾上腺皮质束状带中特异性表达Cre重组酶的转基因动物。采用CRISPR/Cas9技术在CYP11B1基因终止密码子位点定点敲入2A-GfpCre表达框,获得CYP11B1-2A-GfpCre同源重组载体,进而构建CYP11B1Cre小鼠,并通过mTmG和LacZ染色确定Cre酶主要表达在小鼠肾上腺皮质束状带。在此基础上,本研究还用该工具鼠与胱硫醚-γ-裂解酶(cystathionineγ-lyase, CTH)条件性敲除鼠交配,获得了肾上腺皮质束状带CTH特异性敲除的小鼠,并证实了该动物肾上腺皮质束状带中CTH表达缺失。以上结果充分说明肾上腺皮质束状带特异性表达Cre重组酶小鼠构建成功。该工具鼠的成功构建,为深入研究肾上腺皮质束状带相关功能提供了有力工具。  相似文献   

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New aspects on primary aldosteronism   总被引:1,自引:0,他引:1  
The adrenal cortex synthesizes and releases steroid hormones, mainly mineralocorticoids and glucocorticoids. There is a functional zonation of the adrenal cortex and steroid synthesis is thoroughly regulated. Overproduction of aldosterone, primary aldosteronism, may be much more common than previously known and may be responsible for 10% of essential hypertension. Primary aldosteronism is characterized by autonomous production of aldosterone, suppressed renin activity, hypokalemia, and hypertension. The two most common forms are unilateral adenoma and bilateral hyperplasia. In spite of thorough clinical workup and careful histopathology it is often difficult to differentiate between adenoma and hyperplasia. The gene CYP11B2 encodes the steroid synthesizing enzymes for aldosterone production, while the genes CYP17 and CYP11B1 are needed for cortisol production. Most normal controls show expression of CYP11B2 in zona glomerulosa. Expression of CYP11B1 and CYP17 is seen in zona fasciculata and reticularis, whereas the expression of CYP21 is present in all three cortical layers. Adenomas from patients with primary aldosteronism show considerable variation in the expression of CYP11B2. Adenomas from patients with Cushing's syndrome have a strong expression of CYP11B1 and CYP17. In a patient material of 29 cases of primary aldosteronism, 4 patients had small nodules detected with expression of CYP11B2 gene. These nodules were not visualized on CT, whereas adrenal masses seen on CT in these patients showed CYP11B1 and CYP17 gene expression. This suggests that these small nodules are responsible for the aldosterone production and this is characteristic of nodular hyperplasia in patients with primary aldosteronism. In conclusion, this method to visualize mRNA gene expression of steroidogenic enzymes, and especially expression of CYP11B2, has increased the knowledge of adrenal pathophysiology. The results emphasize the value to include functional studies (venous sampling and/or scintigraphy) in the preoperative work up of patients with primary aldosteronism.  相似文献   

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We have investigated the effect of intrafetal cortisol administration, before the normal prepartum cortisol surge, on the expression of 11beta hydroxysteroid dehydrogenase (11betaHSD) type 2 mRNA in the fetal adrenal. We also determined whether increased fetal cortisol concentrations can stimulate growth of the fetal adrenal gland or increase expression of adrenal steroidogenic enzymes. Cortisol (hydrocortisone succinate: 2.0-3.0 mg in 4.4 ml/24 h) was infused into fetal sheep between 109 and 116 days of gestation (cortisol infused; n = 12), and saline was administered to control fetuses (saline infused; n = 13) at the same age. There was no effect of cortisol infusion on the fetal adrenal:body weight ratio (cortisol: 101.7 +/- 5.3 mg/kg; saline: 108.2 +/- 4.3 mg/kg). The ratio of adrenal 11betaHSD-2 mRNA to 18S rRNA expression was significantly lower, however, in the cortisol-infused group (0.75 +/- 0.02) compared with the group receiving saline (1.65 +/- 0.14). There was no significant effect of intrafetal cortisol on the relative abundance of adrenal CYP11A1, CYP17, CYP21A1, and 3betaHSD mRNA. A premature elevation in fetal cortisol therefore resulted in a suppression of adrenal 11betaHSD-2. Increased intra-adrenal exposure to cortisol at this stage of gestation is, however, not sufficient to promote adrenal growth or steroidogenic enzyme gene expression.  相似文献   

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Polymorphysms of the three genes encoding phase 1 (CYP1A1, mEPH1, and CYP2E2) and the three genes encoding phase 2 (NAT2, GSTM1, and GSTT1) xenobiotic detoxication enzymes were typed by use of PCR in 74 patients with extragenital endometriosis. Distribution of the CYP1A1, mEPHX1, CYP2E1, NAT2, and GSTM1 polymorphic alleles in the patient group corresponded to that in the control group. At the same time, functionally defective genotypes GSTM1 0/0, NAT2 S/S; GSTM1 0/0, GSTT1 0/0; and GSTT1 0/0, NAT2 S/S were three, four and eight times more frequent among the patients than in healthy individuals. This observation suggests the existence of a distinct association between the functionally defective alleles of the phase 2 xenobiotic detoxication and endometriosis. Possible mechanisms underlying this association are discussed. It is suggested that typing of the NAT2, GSTM1, and GSTT1 genes can be useful for the assessment of the predisposition to endometriosis.  相似文献   

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Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia, an inherited disorder of cortisol biosynthesis. All mutations thus far characterized that cause this disorder appear to result from recombinations between the gene encoding the enzyme, CYP21B (CYP21), and the adjacent pseudogene, CYP21A (CYP21P). These are either deletions caused by unequal crossing-over during meiosis or apparent transfers of deleterious sequences from CYP21A to CYP21B, a phenomenon termed gene conversion. However, a small percentage of alleles do not carry such a mutation. We analyzed DNA from a patient with the mild, nonclassic form of 21-hydroxylase deficiency, who carried one allele that had no gene conversions detectable by hybridization with oligonucleotide probes. Sequence analysis revealed that this allele carried two missense mutations, R339H and P453S, neither of which has been previously observed in CYP21A or CYP21B. Each of these mutations was introduced into CYP21 cDNA which was then expressed in COS1 cells using a vaccinia virus system. Each mutation reduced the ability of the enzyme to 21-hydroxylate 17-hydroxyprogesterone to 50% of normal and the ability to metabolize progesterone to 20% of normal. Thus, each of these mutations represents a potential nonclassic 21-hydroxylase deficiency allele that is not the result of an apparent gene conversion.  相似文献   

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