Functional consequences of seven novel mutations in the CYP11B1 gene: four mutations associated with nonclassic and three mutations causing classic 11{beta}-hydroxylase deficiency.

CONTEXT: Steroid 11beta-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Cases of nonclassic 11OHD are rare compared with the incidence of nonclassic 21-hydroxylase deficiency. OBJECTIVE: The aim of the study was to analyze the functional consequences of seven novel CYP11B1 mutations (p.M88I, p.W116G, p.P159L, p.A165D, p.K254_A259del, p.R366C, p.T401A) found in three patients with classic 11OHD, two patients with nonclassic 11OHD, and three heterozygous carriers for CYP11B1 mutations. METHODS: We conducted functional studies employing a COS7 cell in vitro expression system comparing wild-type (WT) and mutant CYP11B1 activity. Mutants were examined in a computational three-dimensional model of the CYP11B1 protein. RESULTS: All mutations (p.W116G, p.A165D, p.K254_A259del) found in patients with classic 11OHD have absent or very little 11beta-hydroxylase activity relative to WT. The mutations detected in patients with nonclassic 11OHD showed partial functional impairment, with one patient being homozygous (p.P159L; 25% of WT) and the other patient compound heterozygous for a novel mild p.M88I (40% of WT) and the known severe p.R383Q mutation. The two mutations detected in heterozygous carriers (p.R366C, p.T401A) also reduced CYP11B1 activity by 23 to 37%, respectively. CONCLUSION: Functional analysis results allow for the classification of novel CYP11B1 mutations as causative for classic and nonclassic 11OHD, respectively. Four partially inactivating mutations are predicted to result in nonclassic 11OHD. These findings double the number of mild CYP11B1 mutations previously described as associated with mild 11OHD. Our data are important to predict phenotypic expression and provide important information for clinical and genetic counseling in 11OHD.

[Urinary iodine excretion in German adults in 2005 meets WHO target]. / Jodidurie bei Ewachsenen in Deutschland 2005 im WHO-Zielbereich.

BACKGROUND: Recent regional and Germany-wide investigations have shown that the abolition of the requirement to declare iodine in foodstuffs and the greater emphasis on information about goitre prevention led to an increase in urinary iodine excretion in German schoolchildren. There was also a decrease in thyroid size and goitre prevalence in children. No up-to-date results in adults for the whole of Germany are available. METHODS: In 2005, the authors examined the urinary iodine excretion in the spontaneous morning urine of 1,538 healthy adults in 357 places from all over Germany. The iodine was measured by the cer-arsenite method. RESULTS: The median iodine excretion amounted to 132 microg/l. There were no significant differences between age groups, sexes or regions. 64% had no iodine deficiency (> or = 100 microg/l). In 23% the deficiency was slight (50-99 microg/l), in 10% moderate (20-49 microg/l), and in 3% there was severe iodine deficiency (< 20 microg/l). 29% excreted > 200 microg iodide/l urine. CONCLUSION: According to the WHO (World Health Organization) guidelines, there is no longer an iodine deficiency in German adults.

[No influence of urinary nitrate excretion on the goitre prevalence in Germany]. / Kein relevanter Zusammenhang zwischen Nitraturie und Strumaendemie in Deutschland.

BACKGROUND: It has long been known that nitrate combined with iodiduria < 100 micro gI(-)/l has a goitrogenic effect. The cause is a partial blockage of the sodium- iodide symporter together with a hindrance to iodide absorption in the intestine. 90% of the intake of nitrate is excreted in urine. Therefore nitraturia provides information about the population. The rare epidemiological studies of the influence of NO(3)(-) on goitre are limited to a small selection of older, regional samples. Our aim was to investigate the role of nitrate in the occurrence of goitre in Germany. METHODS: Using random samples from 3,059 clinically healthy persons of both sexes between 18 and 70 years old from all over Germany, we examined nitraturia and the prevalence of goitre or nodules, including the corresponding iodiduria. (Sonography: 7.5 MHz linear transducer; nitrate determination: isocratic ion chromatography; iodide determination: cerium-arsenite method.) Both the NO(3)(-) and the iodide excretion in spontaneous urine were measured in relation to 1 g creatinine. Statistical processing: Mann-Whitney U-Test, correlation analysis, multivariate linear regression analysis. RESULTS: Median for nitraturia: 55.2 mg NO(3)(-)/g creatinine (men 61.5, women 51.5; p < 0.03). Significant increase in regional nitrate excretion from North to South and from East to West. No statistical connection between nitraturia, thyroid size and nodules. In the multivariate linear regression analysis relating to thyroid size/focal lesions, NO(3)(-) played the smallest part among the variables age, gender, body mass index, iodiduria, nitraturia. In the case of iodiduria with < 50 micro g I(-)/g creatinine (n = 71), there was a correlation between nitraturia and thyroid size (r = 0.18; p < 0.05). All persons with a nitraturia of > 60 mg NO(3)(-)/g creatinine (n = 1,166) evidenced a correlation with the thyroid size (r = 0.18; p < 0.01). CONCLUSION: Since alimentary iodine shortage in Germany has been overcome to a large extent (iodiduria 100-200 micro gI(-)/l) and the nitrate content lies clearly below the WHO limit, the goitrogenic effect of nitrate is only of individual and not of epidemiological importance. The slight regional differences in NO(3)(-) excretion are the consequence of the nitrate content in drinking water and have no effect on the thyroid gland.