Disease relevance of CYP11B2

• 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 [1].
• Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2 [2].
• Altered control of aldosterone synthase (CYP11B2) gene expression may modulate aldosterone secretion, as suggested by a raised aldosterone to renin ratio (ARR) in some patients with essential hypertension [3].
• We have studied a patient with congenital adrenal hyperplasia and steroid 11beta-hydroxylase deficiency who was homozygous for a deletion of the CYP11B1 and CYP11B2 genes normally required for cortisol and aldosterone synthesis, respectively [4].
• Apparently the 11beta-hydroxylase deficiency and the adrenal hyperplasia are due to the lack of expression of this gene in the adrenal zona fasciculata/reticularis resulting from replacement of the CYP11B1 promoter and regulatory sequences by those of CYP11B2 [4].

High impact information on CYP11B2

• Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase [5].
• Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase [5].
• A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension [6].
• Genes encoding aldosterone synthase and steroid 11 beta-hydroxylase (expressed in both adrenal fasciculata and glomerulosa), which are 95% identical and lie on chromosome 8q (refs 7, 10), are therefore candidate genes for GRA [6].
• These abnormalities could result from ectopic expression of aldosterone synthase, which is normally expressed only in adrenal glomerulosa, in the adrenal fasciculata [6].
• The expression of aldosterone synthase can be regulated by Purkinje cell protein 4 (PCP4 / PEP-19), voltage-dependent calcium channels (especially CACNA1D and CACNA1H), and a number of G protein-coupled membrane receptors including serotonin-receptor 4 (5-HT4) and metabotropic glutamate receptor 3 (GRM3 / mGluR3) among other neural proteins expressed in the zona glomerulosa of the adrenal and idiopathic hyperaldosteronism, as well as in the cells of aldosterone-producing tumors [7] [8] [9] [10] [11] [12] [13].

Chemical compound and disease context of CYP11B2

• The diagnosis of glucocorticoid-remediable aldosteronism had been traditionally made using the dexamethasone suppression test; however, recent studies have shown that several patients with primary aldosteronism and a positive dexamethasone suppression test do not have the chimeric CYP11B1/CYP11B2 gene [14].
• BACKGROUND: The -344C/T variant in the promoter of the aldosterone synthase gene (CYP11B2) has been associated with hypertension and may influence glucose homeostasis and body mass in humans [15].
• CONCLUSIONS: Compared to a previous smaller study of angiotensin II receptor blockade in essential hypertension, we could not confirm that CYP11B2 -344T/C genotypes contribute towards explaining the observed variability in response to treatment with angiotensin II receptor blockers, which could be due to lack of power [16].
• An infant with failure to thrive, persistent hyponatremia and episodic vomiting and diarrhea was admitted to hospital at 9 months of age, and the diagnosis of type II aldosterone synthase deficiency was confirmed by plasma and urinary steroid determinations [17].
• Corticosterone methyloxidase type I (CMO-I) deficiency is an autosomal recessively inherited disorder causing congenital hypoaldosteronism due to defects in aldosterone synthase (P450aldo), the enzyme that converts 11-deoxycorticosterone to corticosterone, 18-hydroxycorticosterone, and aldosterone [18].

Biological context of CYP11B2

• Cells transfected with hybrid cDNAs containing up to the first three exons of CYP11B1 synthesized aldosterone at levels near that of cells carrying normal CYP11B2, but cells transfected with hybrids containing the first five or more exons of CYP11B1 could not synthesize detectable amounts of aldosterone [2].
• However, the homology between the nucleotide sequences of one of the three and CYP11B2 was rather low, about 90 and 50% in the coding and 0.5-kilobase 5'-flanking regions, respectively [19].
• In transient transfection experiments using mouse adrenocortical Y1 cells and chloramphenicol acetyltransferase gene constructs, the 0.5-kilobase 5'-flanking region of CYP11B1 had a 4- and 10-fold higher promoter activity than the corresponding regions of CYP11B2 and -B3, respectively [19].
• CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity [20].
• The aim of this work was to evaluate whether other genetic alterations exist in CYP11B genes (gene conversion in the coding region of CYP11B1 or in the promoter of CYP11B2) that could explain a positive dexamethasone suppression test and to determine another genetic cause of glucocorticoid-remediable aldosteronism [14].

Anatomical context of CYP11B2

• The final three steps of aldosterone synthesis, 11 beta- and 18-hydroxylation and 18-oxidation, are mediated by a cytochrome P450 in the zona glomerulosa of the adrenal cortex termed CYP11B2 [2].
• A related isozyme in the zona fasciculata, CYP11B1, is required for cortisol synthesis; this isozyme, which is normally expressed at much higher levels than CYP11B2, only has 11 beta-hydroxylase activity [2].
• Therefore, we used immunocytochemistry (ICC) to assess specific zonal localization and developmental regulation of CYP21A2 and CYP11B1/CYP11B2 in the human (13-24 weeks' gestation) and rhesus monkey (109 d-term) fetal adrenal gland [21].
• Using the more sensitive RT-PCR method, transcript for CYP11B2 was found in both neocortex and fetal zone [22].
• The overexpression of CYP11B2 mRNA seen in the mononuclear leukocytes of patients with IHA suggests that unidentified aldosterone-stimulating factors or abnormalities of the CYP11B2 promoter region may cause the overproduction of aldosterone characteristic of IHA [23].

Associations of CYP11B2 with chemical compounds

• CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) are 93% identical mitochondrial enzymes that both catalyze 11beta-hydroxylation of steroid hormones [24].
• CYP11B2 has the additional 18-hydroxylase and 18-oxidase activities required for conversion of 11-deoxycorticosterone to aldosterone [24].
• These two additional C18 conversions can be catalyzed by CYP11B1 if serine-288 and valine-320 are replaced by the corresponding CYP11B2 residues, glycine and alanine [24].
• Although a variant of cAMP-responsive element, which was present in rat CYP11B2 and all known CYP11B genes of other animals, was modified in rat CYP11B1 and -B3 genes, dibutyryl cAMP stimulated all the promoter activities of the 5'-flanking regions of the rat genes by 3-fold [19].
• NGFIB and NURR1 transcript and protein levels were strongly induced by angiotensin (Ang) II, the major regulator of hCYP11B2 expression in vivo [25].

Physical interactions of CYP11B2

• In particular, the Lys173Arg (K173R) polymorphism is in complete genetic linkage disequilibrium with the -344T/C polymorphism in the promoter of CYP11B2 that involves a binding site for the steroidogenic factor-1 transcription factor [26].
• Using an electrophoretic mobility shift assay, we demonstrate that COUP-TFI binds to the -129/-114 element (Ad5) of human CYP11B2 promoter [27].

Regulatory relationships of CYP11B2

• P-450C18 as expressed in COS-7 cells exhibits steroid 18-hydroxylase activity to catalyze the synthesis of aldosterone and 18-oxocortisol and exhibits steroid 11 beta-hydroxylase activity as well [28].
• These data demonstrate that ANG II, K+, and cAMP-signaling pathways utilize the same SF-1 and CRE-like cis-elements to regulate human CYP11B2 expression [29].
• Treatment of H295R cells with calcium/calmodulin-dependent protein kinase (CaMK) inhibitor (KN93) or calmodulin inhibitor (calmidazolium) blocked angiotensin II and potassium (K(+)) stimulation of CYP11B2 reporter gene expression [30].
• Transient transfection in H295R adrenal cells demonstrated that COUP-TFI enhanced CYP11B2 reporter activity [27].
• Tumor necrosis factor reduced ANG II- and potassium-induced aldosterone synthesis and CYP11B2 mRNA levels [31].

Other interactions of CYP11B2

• The extra gene is a hybrid with 5' regulatory and coding regions corresponding to CYP11B1 and 3' coding regions from CYP11B2 [2].
• The competition of human CYP11A1 with human CYP11B1 and CYP11B2 could be diminished with excess expression of bovine adrenodoxin [32].
• Linkage studies in one informative family did not show segregation of FH-II with the CYP11B2, AT1 or MEN1 genes, but a genome-wide search has revealed linkage with a locus in chromosome 7 [33].
• Both DKK3 and WNT4 increased the level of CYP11B2 [34].
• A biallelic gene polymorphism of CYP11B2 predicts increased aldosterone to renin ratio in selected hypertensive patients [3].

Analytical, diagnostic and therapeutic context of CYP11B2

• In all patients we amplified the CYP11B1 gene by PCR and sequenced exons 3-9 of CYP11B1 and a specific region (-138 to -284) of CYP11B2 promoter [14].
• Sequence analysis of CYP11B2 of CMO II deficient patients has revealed two point mutations, CGG-->TGG (Arg181-->Trp) in exon 3 and GTG-->GCG (Val386-->Ala) in exon 7 [35].
• Southern blotting of human genomic DNA digested with StuI suggested the existence of at least four human CYP11B genes [36].
• Body mass index, age, sex, and CYP11B2 genotype displayed no significant effect on the clinical parameters of our population [37].
• In addition, CYP11B2 expression and cardiac fibrosis are found to be decreased in CHF patients on drug therapy comprising spironolactone combined with ACEIs [38].

References