Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated gonadal development and growth in 4 individuals (3 with 46,XY and 1 with 46,XX karyotype) with P450scc deficiency. One patient died at 2 months of age from adrenal insufficiency, while the remaining 3 individuals were healthy and developed normally (age at follow-up: 18, 10 and 8 years). In the surviving individuals, the diagnosis was established during the first 2-4 months of life by extensive endocrine studies of blood and urine. In the remaining patient, the diagnosis was made on the basis of karyotype (46,XY), anatomy of internal and external genitalia and adrenal pathology. Gonadectomy was performed in the 2 surviving 46,XY individuals at the age of 7 years, and histological examination showed normal testicular morphology but very few germ cells. Postmortem examination of the testes of the 2-month-old subject showed normal testicular histology, and quantitative analysis revealed a normal number of germ cells. Ultrasound of the 46,XX individual showed normal internal female genitalia including ovaries with follicles. The 3 surviving patients grew along the 75th (46,XY), the 90th (46,XY) and the 50th percentile (46,XX), respectively. The oldest girl experienced normal breast and pubic hair development after oral estrogen replacement and topical testosterone administration. The glucocorticoid and mineralocorticoid replacement was adjusted in accordance with repeated measurements of serum sodium and serum potassium, plasma renin concentration and blood pressure. No attempts were made to normalize serum ACTH. We conclude that prenatal testicular maturation and development of female internal genitalia may take place in the absence of normal steroid hormone production. Normal growth and development may be obtained in P450scc-deficient individuals with adequate hormone replacement.
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PMID:Gonadal development and growth in 46,XX and 46,XY individuals with P450scc deficiency (congenital lipoid adrenal hyperplasia). 166 80

We studied in vivo and in vitro steroidogenesis in six phenotypic female children with 17-hydroxylase deficiency. The diagnosis was suspected as a likely cause of familial low renin hypertension and was confirmed by findings of reduced basal and ACTH-stimulated serum and urinary levels of cortisol and other 17-hydroxysteroids, together with hypergonadotropic hypogonadism in both 46,XY and 46,XX patients, and abnormally increased secretion of 17-desoxysteroids, such as progesterone, 11-deoxycorticosterone, and corticosterone. ACTH stimulation testing demonstrated a lesser degree of 17-hydroxylase deficiency in the obligate heterozygous parents; one father had increased basal serum 17-hydroxyprogesterone values, unresponsive to ACTH, suggesting partial Leydig cell 17,20-desmolase deficiency. In vitro kinetic analysis of testicular microsomal enzymes in the affected 46,XY male pseudohermaphrodites confirmed that both 17-hydroxylase and 17,20-desmolase activities were less than 2% of those in age-matched normal subjects. However, in spite of this virtual absence of both enzymatic activities of cytochrome P450c17, Northern blot analysis demonstrated abundant amounts of RNA in these tests that hybridized to a cDNA specific for this P450 enzyme. Moreover, immunoblot analysis of sodium dodecyl sulfate-polyacrylamide gel electrophoresis-resolved testicular microsomes showed an apparently normal content of an immunoreactive protein with a mol wt similar to that of authentic P450c17. These results suggest that these patients have a point mutation in the gene for P450c17; the mutant gene is transcribed, but gives rise to a protein defective in normal 17-hydroxylase and 17,20-desmolase activities.
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PMID:Combined 17-hydroxylase and 17,20-desmolase deficiencies: evidence for synthesis of a defective cytochrome P450c17. 249 25

The patient was born with ambiguous genitalia (stade III of Prader). The karyotype revealed a normal female genotype. A defect in 21-hydroxylase, at first suspected, was denied by the hormonal studies. Indeed, extremely high levels of pregnenolone, pregnenolone sulfate, progesterone were found in association with low plasma levels of delta 4-androstenedione, testosterone, dehydroepiandrosterone and its sulfate, while cortisol 17OH-progesterone and ACTH levels and plasma renin activity were normal. The hormonal pattern was thus consistent with 17,20-desmolase deficiency. The dynamic studies further supported this contention: all the progestagens rose further after ACTH stimulation and were suppressed by dexamethasone. Meanwhile, all androgens failed to rise after ACTH: the responses of cortisol were normal. The in utero virilization of the female fetus was not understood until an history of virilization was allegedly found in the mother (luteoma of pregnancy). This is the first case of 17-20 desmolase defect recognized in a female newborn. This child, born with ambiguous genitalia had presented the concurrence of two very rare conditions. The in utero virilization of maternal origin enabled us to make the diagnosis of the 17-20 desmolase defect, which otherwise would have been ignored in a XX subject in the neonatal period because it would obviously be unsymptomatic at this age.
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PMID:17,20-desmolase deficiency in a female newborn, paradoxically virilized in utero. 632 71

We have used several different approaches to study the role of steroids in hypertension, including rodent in vivo models, transgenic animals, and cell culture systems. Using the developing rodent fetus as a model for the ontogeny of regulation of glucocorticoid and mineralocorticoid synthesis, we found that in the developing rodent fetus, expression of both P450scc (cholesterol side chain cleavage) and P450c11 beta (11 beta-hydroxylase) mRNAs occur early, before there is complete organization of the fetal adrenal. Even after the zones of the adrenal are evident, the fetal adrenal still does not express the glomerulosa-specific P450c11AS (aldosterone synthase) mRNA. Stimulating maternal adrenal mineralocorticoid or glucocorticoid synthesis does not affect accumulation of fetal adrenal steroidogenic mRNAs, suggesting that the rodent fetal adrenal may be somewhat transcriptionally quiescent in vivo. We also used two different transgenic rodent systems to study the roles of steroids in hypertension. Using promoter-directed tumorigenesis in transgenic mice, we created transgenic mice that expressed SV40 T antigen under control of the P450scc promoter. Massive adrenal tumors, but not gonadal tumors, developed in all transgenic mice, and cells from these tumors were easily cultured. Using a novel selection tactic, we obtained several adrenocortical cell lines which have distinct characteristics, suggesting they were locked into various stages of differentiation; both expression of steroidogenic mRNAs and the steroids synthesized differ among the lines. Regulation of steroid synthesis and mRNA abundance also varies among cell lines. Several cell lines also express mouse renin, and its synthesis, secretion, and mRNA abundance is also hormonally regulated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Rodent models for studying steroids and hypertension: from fetal development to cells in culture. 779 17

Studies of adrenal steroidogenesis have been facilitated by the availability of immortalized mouse adrenocortical Y-1 cells. We sought to make new, alternative mouse steroidogenic cell lines by genetically targeted tumorigenesis. Transgenic mice were constructed expressing both the SV40 T-antigen and a bacterial neomycin-resistance gene under the control of the promoter for the human P450 cholesterol side-chain cleavage (P450scc) gene, which encodes the first and rate-limiting enzyme in steroidogenesis. Two female transgenic mice expressed T-antigen in various nonsteroidogenic tissues but generated tumors only in the adrenals, suggesting adrenal tumor formation was an early event. Ovarian tissues, which, unlike the adrenal, do not make steroids in fetal or early postnatal life, did not develop tumors. Cell lines derived from the adrenal tumors were resistant to the neomycin analog G418. Clonal sublines are stable, growing easily in monolayers with a doubling time of 24-60 h. The cell lines secrete progesterone and 11-deoxycorticosterone, indicating these cells express the P450scc system, 3 beta-hydroxysteroid dehydrogenase, and 21-hydroxylase activity. However the 21-hydroxylase activity was not mediated by P450c21, as the cells lacked P450c21 mRNA. The cells did not secrete any 11-hydroxylated steroids, although they contained P450c11 beta mRNA. Both the secretion of progesterone and the abundance of P450scc mRNA increase in response to 8-bromo-cAMP, but not to ACTH or angiotensin II. In addition to expression of steroidogenic enzyme mRNAs, one cell line also expresses mouse renin-1 mRNA, making these cells useful for studies of the role of adrenal renin in regulating adrenal steroidogenesis. These findings represent an approach in transgenic mice to develop highly differentiated adrenal cell lines.
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PMID:Steroidogenic adrenocortical cell lines produced by genetically targeted tumorigenesis in transgenic mice. 815 34

The major regulator of mineralocorticoid production in the adrenal is angiotensin II produced by the action of renal renin. The discovery that the rodent adrenal also synthesizes renin and angiotensinogen suggests there is autocrine regulation of mineralocorticoid synthesis. The transgenic rat [TGR(mREN2)27] expresses the Ren-2d gene predominantly in the adrenal. Despite suppressed kidney and plasma renin, these animals develop fulminant hypertension between 5 and 15 weeks of age. Corticosteroid concentrations are significantly elevated during hypertension development. We assessed steroidogenesis in TGR(mREN2)27 rats by analyzing the expression of the mRNAs for three steroidogenic enzymes: P450scc, the rate-limiting step of steroidogenesis; P450c11 beta, which converts deoxycorticosterone to corticosterone in the zona fasciculata/reticularis; and P450c11AS, which converts deoxycorticosterone to aldosterone in the zona glomerulosa. P450c11AS mRNA, but neither P450c11 beta nor P450scc mRNA, was overexpressed in the adrenal gland of TGR(mREN2)27 rats. In situ hybridization with specific probes for P450c11 beta and P450c11AS mRNA localized the former exclusively to the zona fasciculata and the latter to the zona glomerulosa. In TGR(mREN2)27 rats, the size of the adrenal and number of P450c11AS-expressing zona glomerulosa cells were about twice those of a normal Sprague-Dawley rat. Both animals respond to corticotropin similarly; corticotropin had no effect on the expression of P450scc and P45011 beta mRNAs, rendered P450c11AS mRNA undetectable, and simultaneously altered the morphology of the adrenal cortex, resulting in a lack of zona glomerulosa-like cells. Thus, the local renin-angiotensin system has a major effect on the basal expression of P450c11AS mRNA, but little effect on the corticotropin-regulated expression of P450scc, P450c11 beta, and P450c11AS mRNAs.
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PMID:Role of adrenal renin in the regulation of adrenal steroidogenesis by corticotropin. 827 56

A 29-year-old woman with deoxycorticosterone (DOC)-producing adrenocortical adenoma had hypertension and hypokalemia but without Cushingoid features. Plasma renin activity and the aldosterone concentration were low, while the DOC concentration was high (6.10-10.3 ng/ml; normal range 0.03-0.33). Plasma cortisol, androgens, and estrogens as well as urinary 17-OHCS and 17-KS were within normal limits. Furosemide administration and two hours upright posture resulted in a 3-fold increase in plasma DOC, but the administration of ACTH, dexamethasone, or angiotensin III had no effect on plasma DOC. Following resection of a right adrenal tumor weighing 70 g, the hypertension and hypokalemia disappeared. DOC content in the tumor was high. On light microscopic examination, the tumor was encapsulated, composed of cells with clear cytoplasm and large nuclei and there were extensive areas of fibrosis and infiltration of lymphocytes. According to Weiss's criteria, the tumor was considered to be an adrenocortical adenoma. Immunohistochemically, P450scc, 3 beta HSD, P450C21 and P45011 beta were positive with heterogeneity of intra-tumoral expression. No immunoreactivity for P45017 alpha in this adenoma was detected. This is different from a previous report in which a relatively small number of cells in DOC-secreting adrenocortical carcinoma were positive for P45017 alpha.
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PMID:A case of deoxycorticosterone-producing adrenal adenoma. 857 86

There are two main regulatory sites of aldosterone biosynthesis, the early rate-limiting step by the P450scc and the final steps by the P450aldo. We have already demonstrated that, during gestation, activity and mRNA levels of P450aldo are increased. It has been shown that changes in sodium and potassium in the diet modulate the expression of P450aldo in adrenal zona glomerulosa (ZG). In the present study, we compared the effects of low-sodium (Na+) and high-potassium (K+) diet on the expression of enzymes controlling aldosterone synthesis during gestation. Pregnant and nonpregnant rats were randomly assigned to control group or to group receiving low Na+ or high K+ diet during the last week of pregnancy. By the end of the treatment, the two diets induced increases of plasma aldosterone and P450aldo mRNA levels in nonpregnant and pregnant rats. However, plasma renin activity and P450scc mRNA levels were only in the pregnant group fed the low Na+ diet. High K+ diet had no effect on these parameters. We, thus, suggest that the renin-angiotensin system and the enzymes implicated in aldosterone synthesis are differently regulated during gestation.
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PMID:In vivo regulation of enzymes controlling aldosterone synthesis in pregnant rats. 988 40

During testicular development, fetal and adult populations of Leydig cells arise sequentially. Previous studies have shown that androgen action is required for normal steroidogenic activity in the mouse testis. Therefore, to determine the role of androgens in regulating fetal and adult Leydig cell differentiation and function, Leydig development has been measured in mice lacking functional androgen receptors (AR-null). The Leydig cell number was normal on day 5 after birth in AR-null mice but failed to increase normally thereafter and was about 30% of the control level on day 20 and about 60% of control level in adult animals. Levels of 15 different mRNA species expressed specifically in Leydig cells were measured by real-time PCR in AR-null and control animals. Expression levels of all mRNA species were normal on day 5 when only fetal Leydig cells are present. In older animals, which contain predominantly adult Leydig cells, five of the mRNA species (3beta-hydroxysteroid dehydrogenase (3betaHSD) type 1, cytochrome P450scc, renin, StAR protein and luteinising hormone receptor) were expressed at normal or increased levels in AR-null mice. All other mRNA species measured showed significantly reduced expression in older animals, and three of these mRNA species (17beta-hydroxysteroid dehydrogenase type III, prostaglandin D (PGD)-synthetase and 3betaHSD type VI), which are only expressed in the adult population of Leydig cells, were barely detectable in the adult AR-null mouse. The results show that in the absence of androgen receptors, fetal Leydig cell function is normal, but there is a developmental failure of adult Leydig cell maturation, with cells only aquiring partial characteristics of the adult population.
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PMID:Failure of normal adult Leydig cell development in androgen-receptor-deficient mice. 1215 79

Steroidogenic acute regulatory protein (StAR) plays a crucial role in the transport of cholesterol from the cytoplasm to the inner mitochondrial membrane, facilitating its conversion to pregnenolone by cytochrome P450scc. Its essential role in steroidogenesis was demonstrated after observing that StAR gene mutations gave rise to a potentially lethal disease named congenital lipoid adrenal hyperplasia, in which virtually no steroids are produced. We report here a 2-month-old female patient, karyotype 46XY, who presented with growth failure, convulsions, dehydration, hypoglycemia, hyponatremia, hypotension, and severe hyperpigmentation suggestive of adrenal insufficiency. Serum cortisol, 17OH-progesterone, dehydroepiandrosterone sulfate, testosterone, 17OH-pregnenolone, and aldosterone levels were undetectable in the presence of high ACTH and plasma renin activity levels. Immunohistochemical analysis of testis tissues revealed the absence of StAR protein. Molecular analysis of StAR gene demonstrated a homozygous G to T mutation within the splice donor site of exon 1 (IVS1 + 1G>T). Her parents and one brother were heterozygous for this mutation. In vitro analysis of the mutation was performed in COS cells transfected with minigenes coding regions spanning exon-intron 1 to 3 carrying the mutant and the wild-type sequences. RT-PCR analyses of the mutant gene showed an abnormal mRNA transcript of 2430 bp (normal size 433 bp). Sequence analysis of the mutant mRNA demonstrated the retention of intron 1. Immunolocalization of the StAR minigene product detected the peptide in the mitochondria of COS cells transfected with the wild-type minigene but not in those transfected with the mutant minigene. We conclude that this mutation gives rise to a truncated StAR protein, which lacks an important N-terminal region and the entire lipid transfer domain.
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PMID:Congenital lipoid adrenal hyperplasia caused by a novel splicing mutation in the gene for the steroidogenic acute regulatory protein. 1476 19


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