Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoid-suppressible hyperaldosteronism (GSH) is one variety of primary aldosteronism with hypertension and is inherited in an autosomal dominant mode. A recent report has indicated that GSH is caused by a gene duplication arising from unequal crossing over between the two genes, CYP11B1 and CYP11B2, encoding P-450(11 beta) and P-450C18, respectively (Lifton et al. Nature (1992) 355, 262-265). The nucleotide sequence analysis in the present study has demonstrated that unequal crossing over in the chimeric gene formed by the gene duplication occurs within the region from the 3'-portion of exon 4 through the 5'-portion of intron 4 in Australian GSH patients. Namely, the chimeric gene encodes a fused P-450 protein consisting of the amino-terminal side of P-450(11 beta) (encoded by exons 1-4 of CYP11B1) and the carboxyl-terminal side of P-450C18 (encoded by exons 5-9 of CYP11B2). When a cDNA corresponding to the chimeric gene is transfected into COS-7 cells, the fused P-450 protein expressed in the mitochondria exhibits steroid 18-hydroxylase or aldosterone synthase activity. These results provide the molecular genetic basis for the characteristic biochemical phenotype of GSH patients.
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PMID:The chimeric gene linked to glucocorticoid-suppressible hyperaldosteronism encodes a fused P-450 protein possessing aldosterone synthase activity. 147 60

Clinical, biochemical and molecular data on five kindreds with dexamethasone-suppressible hyperaldosteronism are reviewed. The clinical phenotype varies from severe, early onset hypertension to much milder blood pressure elevation; hypokalaemia is usually mild. The genetic basis of the syndrome reflects the presence of a chimaeric gene derived from an unequal crossover between CYP11B1 and CYP11B2, resulting in ACTH-sensitive aldosterone synthase activity. In five kindreds, at least three different mutations have been identified, suggesting that allelic predisposition might lead to increased geographical prevalence of the condition in Celtic populations.
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PMID:Dexamethasone-suppressible hyperaldosteronism: clinical, biochemical and genetic relations. 747 36

Polymorphisms affecting the synthesis of aldosterone or its regulation may have effects on blood pressure. For example, an autosomal dominant form of human hypertension, glucocorticoid suppressible hyperaldosteronism, is caused by recombination between the genes for aldosterone synthase (CYP11B2) and steroid 11 beta-hydroxylase (CYP11B1), creating a chimeric gene in which the CYP11B1 promoter and CYP11B2-specific coding sequences are juxtaposed. Thus, aldosterone synthesis is improperly regulated. We have begun an analysis of the human CYP11B2 and CYP11B1 genes to see if frequent polymorphisms exist and if they are correlated with differences in blood pressure. We have found frequent polymorphisms in CYP11B2. One in the promoter influences binding of the transcriptional regulatory protein, SF-1. Another is a gene conversion in intron 2 so that most of the intron has a sequence corresponding to CYP11B1. These polymorphisms are in linkage disequilibrium, defining 3 haplotypes. Blacks and whites differ significantly (p < 0.001) in the frequency with which these haplotypes occur. Further studies are required to determine if the observed differences between blacks and whites in blood pressure and in aldosterone levels can be explained in part by these allelic differences in CYP11B2 or by other polymorphisms in linkage disequilibrium on these haplotypes.
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PMID:Haplotype analysis of CYP11B2. 758 7

Glucocorticoid-suppressible hyperaldosteronism is a dominantly inherited form of hypertension believed to be caused by the presence of a hybrid CYP11B1/CYP11B2 gene which has arisen from an unequal crossing over between the two CYP11B genes in a previous meiosis. We have studied a French pedigree with seven affected individuals in which two affected individuals also have adrenal tumors and two others have micronodular adrenal hyperplasia. One of the adrenal tumors and the surrounding adrenal tissue has been removed, giving a rare opportunity to study the regulation and action of the hybrid gene causing the disease. The hybrid CYP11B gene was demonstrated to be expressed at higher levels than either CYP11B1 or CYP11B2 in the cortex of the adrenal by RT-PCR and Northern blot analysis. In situ hybridization showed that both CYP11B1 and the hybrid gene were expressed in all three zones of the cortex. In cell culture experiments hybrid gene expression was stimulated by ACTH leading to increased production of aldosterone and the hybrid steroids characteristic of glucocorticoid-suppressible hyperaldosteronism. The genetic basis of the adrenal pathologies in this family is not known but may be related to the duplication causing the hyperaldosteronism.
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PMID:Glucocorticoid-suppressible hyperaldosteronism and adrenal tumors occurring in a single French pedigree. 759 10

The most active corticosteroids are 11 beta-hydroxylated. Humans have two isozymes with 11 beta-hydroxylase activity that are respectively required for cortisol and aldosterone synthesis. CYP11B1 (11 beta-hydroxylase) is expressed at high levels and is regulated by ACTH, whereas CYP11B2 (aldosterone synthase) is normally expressed at low levels and is regulated by angiotensin II. In addition to 11 beta-hydroxylase activity, the latter enzyme has 18-hydroxylase and 18-oxidase activities and thus can synthesize aldosterone from deoxycorticosterone. Insights into the normal functioning of these enzymes are gained from studies of disorders involving them. Mutations in the CYP11B1 gene cause steroid 11 beta-hydroxylase deficiency, a form of congenital adrenal hyperplasia characterized by signs of androgen excess and by hypertension. Mutations in CYP11B2 result in aldosterone synthase (corticosterone methyloxidase) deficiency, an isolated defect in aldosterone biosynthesis that can cause hyponatremia, hyperkalemia, and hypovolemic shock in infancy and failure to thrive in childhood. These are both recessive disorders. Unequal crossing over between the CYP11B genes can generate a duplicated chimeric gene with the transcriptional regulatory region of CYP11B1 but sufficient coding sequences from CYP11B2 so that the encoded enzyme has aldosterone synthase (i.e. 18-oxidase) activity. This results in aldosterone biosynthesis being regulated by ACTH, a condition termed glucocorticoid-suppressible hyperaldosteronism. This form of genetic hypertension is inherited in an autosomal dominant manner.
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PMID:Disorders of steroid 11 beta-hydroxylase isozymes. 798 80

Steroid 11 beta-hydroxylase deficiency is the second most frequent cause of congenital adrenal hyperplasia, the inherited inability to synthesize cortisol. About two thirds of patients with this disorder have hypertension, presumably due to elevated levels of deoxycorticosterone or other metabolites. Signs of androgen excess also often are prominent. This disease is caused by mutations in the CYP11B1 gene, which encodes a mitochondrial cytochrome P450 enzyme. The main treatment is glucocorticoid replacement, which suppresses excessive secretion of mineralocorticoids and androgens by the adrenal cortex.
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PMID:Steroid 11 beta-hydroxylase deficiency and related disorders. 807 Apr 25

Steroid 11 beta-hydroxylase is encoded by two homologous genes, CYP11B1 and CYP11B2, located on chromosome 8q21-22. CYP11B1 encodes a specific cytochrome P-450 (P-450c11) necessary for cortisol biosynthesis, with predominantly 11 beta-hydroxylase and moderate 18-hydroxylase activity, whereas CYP11B2 encodes another isozyme (P-450cmo) necessary for aldosterone biosynthesis, with 11 beta-hydroxylase, 18-hydroxylase and 18-oxidase activities (the latter two termed corticosterone methyl-oxidase I and II; CMO-I and II, respectively). Two steroid biosynthetic defects, both relatively frequent in Israel, are caused by specific mutations in each of these genes. 11 beta-Hydroxylase deficiency is frequent among Jews from Morocco (1 in 5000 to 7000 births), and is characterized by virilization, hypertension, impaired cortisol biosynthesis, and increased deoxycorticosterone and androgens. Affected individuals have a single base substitution in exon 8 of CYP11B1, codon 448, from CGC (arginine) to CAC (histidine). This sequence, normally absent in CYP11B2, constitutes a true point mutation within the heme binding domain of CYP11B1 that results in marked impairment of enzymatic activity. The clinical expression is characterized by a wide range of variability in the signs of both androgen and mineralocorticoid excess, even though an identical mutation was found in all but one of the affected alleles examined. CMO-II deficiency is frequent among Jews from Iran (1 in 4000 births), and is characterized by a typical salt-wasting syndrome, increased 18-hydroxycorticosterone, impaired aldosterone biosynthesis, and a high ratio of these steroids. No mutation was found in CYP11B1, but all individuals affected were homozygous for two missense mutations in CYP11B2. The first, in exon 3, codon 181, from CGG (arginine) to TGG (tryptophane) is a mutation that completely abolishes both CMO-I and II activities, whereas the second, in exon 7, codon 386, from GTG (valine) to GCG (alanine) is a more conservative substitution that produces only a minimal reduction in CMO-I activity. Individuals homozygous for either one of these mutations are asymptomatic.
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PMID:Mutations in human 11 beta-hydroxylase genes: 11 beta-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran. 848 57

The biosynthesis of glucocorticoids and mineralocorticoids requires isozymes of P450c11. Two human isozymes are known: P450c11 beta, encoded by the CYP11B1 gene, has 11 beta-hydroxylase activity; P450c11AS, encoded by the CYP11B2 gene, has 11 beta-hydroxylase, 18-hydroxylase, and aldosterone synthase activities. Recent data show that the rat genome has four CYP11B genes, three of which are functional, and one of which has novel behaviors. As the number of human CYP11B genes was unknown and as the existence of novel P450c11 isozymes might have implications in the study of hypertension, we sought to determine if the human genome, like the rat genome, contained more than two CYP11B genes. Southern blotting of human genomic DNA digested with StuI suggested the existence of at least four human CYP11B genes. Similar analysis of cosmid clones suggested multiple CYP11B genes. However, cloning and sequencing of the multiple hybridizing fragments showed that there are only two CYP11B genes in the human genome, and that the "extra" bands seen were due to spurious hybridization. The absence of additional CYP11B genes in the human genome analogous to those in the rat narrows the search for genes that contribute to low renin hypertension.
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PMID:The human genome contains only two CYP11B (P450c11) genes. 878 78

Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal convoluted tubules and cortical collecting ducts. Excess secretion of aldosterone or other mineralocorticoids or abnormal sensitivity to mineralocorticoids may result in hypertension, suppressed plasma renin activity, and hypokalemia. Such conditions often have a genetic basis, and studies of these conditions have provided valuable insights into the normal and abnormal physiology of mineralocorticoid action. Deficiencies of steroid 11 beta-hydroxylase or 17 alpha-hydroxylase are types of congenital adrenal hyperplasia, the autosomal recessive inability to synthesize cortisol. These two defects often cause hypertension because of overproduction of cortisol precursors that are, or are metabolized to, mineralocorticoid agonists. These disorders result from mutations in the CYP11B1 and CYP17 genes encoding the corresponding enzymes. Glucocorticoid-suppressible hyperaldosteronism is an autosomal dominant form of hypertension in which aldosterone secretion is abnormally regulated by corticotropin. It is caused by recombinations between linked genes encoding closely related isozymes, 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), generating a dysregulated chimeric gene with aldosterone synthase activity. Apparent mineralocorticoid excess is a loss of functional ligand specificity of the mineralocorticoid receptor caused by a deficiency of the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase, an enzyme that normally metabolizes cortisol to cortisone to prevent cortisol from occupying the receptor. This autosomal recessive form of severe hypertension results from mutations in the HSD11K (HSD11B2) gene.
Hypertension 1996 Dec
PMID:Inherited forms of mineralocorticoid hypertension. 895 79

The possibility that adrenocorticosteroids might be synthesized in the central nervous system was assessed by RT-PCR using primers for the CYP11B1 gene which codes for 11 beta-hydroxylase, the enzyme responsible for corticosterone and cortisol formation in the zona fasciculata, incubation of minces of several areas of the brain with 3H-DOC and measuring steroid metabolites, and determining the effect of the intracerebroventricular infusion of the 11 beta-hydroxylase mechanism-based inhibitor 19-ethynyldeoxycorticosterone upon the salt-induced increase in blood pressure in SS/jr rats. Significant, though small relative to the adrenal, amounts of mRNA for 11 beta-hydroxylase was found in the aorta, cerebrum, cerebellum, hippocampus, hypothalamus and amygdala, but not in the heart. Brain minces converted 3H-DOC to corticosterone and 11-dehydrocorticosterone to a greater degree than to 18-OH-DOC. The effect of 19-ethynyldeoxycorticosterone was dose dependent, with the lower doses preventing salt-induced hypertension and the higher doses having no effect or increasing the blood pressure.
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PMID:Corticosteroid synthesis in the central nervous system. 896 97


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