Peter M, Sippell W G
Division of Pediatric Endocrinology, Department of Pediatrics, Christian-Albrechts-University of Kiel, Germany.
Pediatr Res. 1996 Mar;39(3):554-60. doi: 10.1203/00006450-199603000-00027.
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.
1964年，H. K. A. 维瑟和W. S. 科斯特首次提出醛固酮分泌减少症患者存在终末醛固酮生物合成缺陷。近年来，终末醛固酮生物合成的分子基础已被阐明。醛固酮生物合成需要将11-脱氧皮质酮进行11β-羟化以形成皮质酮，在C-18位进行羟化以形成18-羟皮质酮（18-OHB），最后在C-18位进行氧化。一种单一的细胞色素P450酶（P450aldo）催化球状带中的所有这三个反应。编码基因称为CYP11B2。已经描述了两种终末醛固酮生物合成的先天性错误，其特征是皮质酮产生过多和醛固酮合成不足。I型皮质酮甲基氧化酶缺乏症（CMO I）的特点是18-OHB产生减少，而CMO II的特点是18-OHB产生过多以及18-OHB与醛固酮的比例升高。这两种疾病均通过常染色体隐性遗传，在婴儿早期会导致失盐和发育不良。我们目前的系列研究包括14例通过多类固醇分析（提取后放射免疫分析和自动高效凝胶色谱法）诊断的CMO缺乏婴儿，该方法为区分两种CMO变体提供了精确的生化标准。到目前为止，已经描述了P450aldo缺乏症患者CYP11B2基因内的三种不同突变。将这些突变引入CYP11B2 cDNA表达载体构建体并随后在COS细胞中表达，显示P450aldo的11β-羟化酶、18-羟化酶和18-脱氢酶活性丧失。对更多P450aldo缺乏症患者进行进一步的分子研究，未来可能会澄清CYP11B2（P450aldo）结构-功能关系中仍然存在的差异。
