Congenital hypoaldosteronism: the Visser-Cost syndrome revisited.
In 1964, H. K. A. Visser and W. S. Cost were the first to suggest a defect of the terminal aldosterone (Aldo) biosynthesis in patients with hypoaldosteronism. In the last years, the molecular basis of the terminal Aldo biosynthesis has been elucidated. Aldo biosynthesis requires 11beta-hydroxylation of 11-deoxycorticosterone to form corticosterone, hydroxylation at position C-18 to form 18-hydroxycorticosterone (18-OHB), and finally oxidation at position C-18. One single cytochrome P450 enzyme (P450aldo) catalyzes all three reactions in the zona glomerulosa. The coding gene is termed CYP11B2. Two inborn errors of terminal Aldo biosynthesis characterized by overproduction of corticosterone and deficient synthesis of Aldo have been described. Corticosterone methyl oxidase deficiency type I (CMO I) is distinguished by decreased production of 18-OHB while CMO II is characterized by overproduction of 18-OHB and an elevated ratio of 18-OHB to Aldo. Both disorders are inherited by an autosomal recessive trait and cause salt-wasting and failure to thrive in early infancy. Our present series includes 14 CMO deficient infants diagnosed by multisteroid analysis (RIA after extraction and automated high performance gel chromatography) which provides precise biochemical criteria for the differentiation of the two CMO variants. So far, three different mutations within the CYP11B2 gene in patients with P450aldo deficiency have been described. Introduction of these mutations into a CYP11B2 cDNA expression vector construct and subsequent expression in COS cells revealed loss of 11beta-hydroxylase, 18-hydroxylase, and 18-dehydrogenase activity of P450aldo. Further molecular studies on more P450aldo-deficient patients might clarify in the future the still existing discrepancies in CYP11B2 (P450aldo) structure-function relationship.
Peter
M
M
Division of Pediatric Endocrinology, Department of Pediatrics, Christian-Albrechts-University of Kiel, Germany.
Sippell
W G
WG
D000450:Aldosterone / Q000096:biosynthesis*; D002675:Child, Preschool; D019405:Cytochrome P-450 CYP11B2; D005260:Female; D006801:Humans; D006994:Hypoaldosteronism / Q000151:congenital*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D006899:Mixed Function Oxygenases / Q000172:deficiency* / Q000378:metabolism; D013577:Syndrome
D000450:Aldosterone; D006899:Mixed Function Oxygenases; D019405:Cytochrome P-450 CYP11B2; C033112:corticosterone methyl oxidase I; C025352:corticosterone methyl oxidase II