Potential advantage of N363S glucocorticoid receptor polymorphism in 21-hydroxylase deficiency.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) shows a range of severity which is explained in part by the different mutations of the CYP21 gene. To better understand the incomplete concordance between genotype and phenotype in CAH the role of the sensitizing N363S polymorphism of the glucocorticoid receptor (GR) was examined in CAH patients. DESIGN: CAH patients were screened for N363S. Laboratory findings and clinical characteristics of carriers and non-carriers were analyzed retrospectively. METHODS: The CYP21 gene of 200 CAH patients was analyzed by allele-specific PCR. The GR gene was tested for N363S by PCR followed by restriction fragment length polymorphism. Antropometric data (height, weight), degree of intrauterine virilization, hormone concentrations (17-OH-progesterone, dehydroepiandrosterone (DHEA), aldosterone, testosterone, plasma renin activity), substitution doses and clinical course were analyzed. RESULTS: The carrier frequency of N363S in CAH patients was equivalent to that of the general Hungarian population (6% vs 7.8%). Interestingly, none of the non-classical CAH (NC-CAH) patients were carriers of the polymorphism. Carrier girls had milder genital virilization than mutation-matched non-carrier controls. There was no significant difference between the carriers and non-carriers in either the substitution doses, the hormonal, or the auxiological parameters. CONCLUSIONS: The association of sensitizing the GR variant with impaired cortisol production in CAH might be compensatory in mild NC-CAH and may prevent severe intrauterine virilization in classical form. Although the exact role of N363S in extrauterine life should be further investigated, the consideration of certain genetic polymorphisms of CAH patients may lead to better, individualized therapeutic regimes.

A model for the catabolism of rhizopine in Rhizobium leguminosarum involves a ferredoxin oxygenase complex and the inositol degradative pathway.

Rhizopines are nodule-specific compounds that confer an intraspecies competitive nodulation advantage to strains that can catabolize them. The rhizopine (3-O-methyl-scyllo-inosamine, 3-O-MSI) catabolic moc gene cluster mocCABRDE(F) in Rhizobium leguminosarum bv. viciae strain 1a is located on the Sym plasmid. MocCABR are homologous to the mocCABR gene products from Sinorhizobium meliloti. MocD and MocE contain motifs corresponding to a TOL-like oxygenase and a [2Fe-2S] Rieske-like ferredoxin, respectively. The mocF gene encodes a ferredoxin reductase that would complete the oxygenase system, but is not essential for rhizopine catabolism. We propose a rhizopine catabolic model whereby MocB transports rhizopine into the cell and MocDE and MocF (or a similar protein elsewhere in the genome), under the regulation of MocR, act in concert to form a ferredoxin oxygenase system that demethylates 3-O-MSI to form scyllo-inosamine (SI). MocA, an NAD(H)-dependent dehydrogenase, and MocC continue the catabolic process. Compounds formed then enter the inositol catabolic pathway.

Clinical and biochemical features of sporadic and hereditary phaeochromocytomas: an analysis of 41 cases investigated in a single endocrine centre.

The aims of this study were to estimate the prevalence of phaeochromocytomas among adrenal tumours and to analyse the clinical and biochemical features of sporadic and hereditary tumours. Our series of 609 adrenal tumours evaluated between January 1995 and July 2003 was reviewed. Catecholamine content in phaeochromocytoma tissues was also determined and correlated with clinical behaviour and biochemical parameters of patients. Forty-one (6.7%) of the 609 patients had phaeochromocytomas, of which 28 were sporadic (25 benign and three malignant) and 13 (all benign) were associated with hereditary diseases (multiple endocrine neoplasia type 2A in seven cases from four unrelated families carrying mutations of the RET gene, von Hippel-Lindau disease in two unrelated cases with mutations of the VHL gene, and type 1 neurofibromatosis in four unrelated cases). Bilateral tumours were found in three patients with hereditary syndromes and in one sporadic case. Tumour diameter was slightly but not significantly greater in patients with hereditary than in those with sporadic tumours. Systolic but not diastolic blood pressure was significantly higher in patients with sporadic compared with those with hereditary tumours, but comparison of other clinical data and biochemical parameters indicated an absence of significant differences in the mean age, presenting symptoms, heart rate, or fasting serum glucose levels. Tissue catecholamine content measured in 8 sporadic and 5 hereditary phaeochromocytomas was highly variable and it failed to show significant differences between hereditary and sporadic tumours. These results indicate a high proportion of hereditary diseases among patients with phaeochromocytomas. Genetic and clinical testing for hereditary diseases may be of great help to offer an appropriate treatment, follow-up and family screening for these patients.

Conservation of a pseudomonad-like hydrocarbon degradative ferredoxin oxygenase complex involved in rhizopine catabolism in Sinorhizobium meliloti and Rhizobium leguminosarum bv. viciae.

In Sinorhizobium meliloti the mocCABR genes have previously been shown to be required for rhizopine (3-O-methyl-scyllo-inosamine, 3-O-MSI) catabolism. We show that the mocDE(F) gene cluster is also needed. MocDE(F), which is involved in the catabolism of 3-O-MSI to its demethylated form scyllo-inosamine (SI) has homology to components that would comprise a ferredoxin-oxygenase system. The mocCABRDE(F) suite of genes is required for 3-O-MSI catabolism in both S. meliloti and R. leguminosarum bv. viciae. However, SI catabolism in S. meliloti requires mocCABR, whereas only mocCA are required for its catabolism in R. leguminosarum suggesting the two species require different chromosomal genes which act in concert with moc genes for the catabolism of rhizopine.

Effect of single doses of dexamethasone and adrenocorticotrop hormone on serum bone markers in healthy subjects and in patients with adrenal incidentalomas and Cushing's syndrome.

The aim of the present study was to explore whether short-term changes in glucocorticoid activity which occur during dynamic testing of the pituitary adrenal axis with dexamethasone, ACTH, or metyrapone could have an effect on serum osteocalcin (OC) and beta-crosslaps (beta-CTx) concentrations in healthy subjects, in patients with adrenal incidentalomas and in those with Cushing's syndrome. The study included 40 healthy subjects (35 women and 5 men, age range 18-69 yr), 49 patients with adrenal incidentalomas (34 women and 15 men, age range 19-77 yr) and 8 patients with Cushing's syndrome (5 cortisol-producing adenomas and 3 pituitary-dependent Cushing's syndrome, 3 women and 5 men, age range 19-70 yr). Serum OC and beta-CTx concentrations were determined with electrochemoluminescent immunoassays at midnight, after an overnight fast between 08:00 and 09:00 h, after an overnight dexamethasone test (1 mg, orally) and after a single dose of metyrapone (30 mg/kg, orally). In healthy subjects and in patients with adrenal incidentalomas, serum bone marker concentrations were also measured after a single dose of ACTH injection (Cortrosyn depot, 1 mg im). Patients with Cushing's syndrome, but not those with adrenal incidentalomas, showed significantly lower serum OC at midnight (18.5+/-12 ng/ml, mean+/-SD) and between 08:00 and 09:00 h (17.7+/-9.6 ng/ml) compared to corresponding values obtained in healthy subjects (24.5+/-7.0 and 28.3+/-12.2 ng/ml, respectively). Serum OC concentrations were significantly decreased after a single dose of 1-mg dexamethasone in healthy subjects (from 28.3+/-12.2 to 21.8+/-9.5 ng/ml) and in patients with adrenal incidentalomas (from 29.8+/-15.9 to 24.1+/-14.1 ng/ml), whereas serum OC concentrations remained unchanged in patients with Cushing's syndrome. In addition, serum OC concentrations were even more markedly decreased after a single dose of ACTH injection in both healthy subjects (12.5+/-4.6 ng/ml) and in patients with adrenal incidentalomas (12.2+/-6.5 ng/ml). By contrast, metyrapone administration failed to induce significant changes in OC levels. There were no significant differences in beta-CTx concentrations between the three groups or after drug treatments. Thus, serum OC levels should be interpreted with caution when obtained during testing of the pituitary-adrenal axis with dexamethasone or ACTH.