MUTATIONS IN THE HUMAN CYP11B2 (ALDOSTERONE SYNTHASE) GENE CAUSING CORTICOSTERONE METHYLOXIDASE-II DEFICIENCY
MUTATIONS IN THE HUMAN CYP11B2 (ALDOSTERONE SYNTHASE) GENE CAUSING CORTICOSTERONE METHYLOXIDASE-II DEFICIENCY
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DOI：
10.1073/pnas.89.11.4996
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发表时间：
1992-06-01
影响因子：
11.1
通讯作者：
WHITE, PC
中科院分区：
文献类型：
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作者：
PASCOE, L;CURNOW, KM;WHITE, PC
皮质酮甲基氧化酶II（CMO-II）缺乏症是一种常染色体隐性遗传的醛固酮生物合成障碍，其特征是血清中18-羟皮质酮与醛固酮的比例升高。它与CYP 11B 1和CYP 11B 2基因遗传连锁，分别编码两种细胞色素P450同工酶P450 XIB 1和P450 XIB 2。P450 XIB 1仅催化11-脱氧皮质酮和11-脱氧皮质醇的11-β位的羟基化，而P450 XIB 2催化从脱氧皮质酮合成醛固酮，该过程依次需要11-β位和18位的羟基化和18位的氧化。为了确定CMO-II缺乏症的分子遗传学基础，研究了7个伊朗-犹太血统的家族，其中成员患有CMO-II缺乏症。在CYP 11B 1基因中未发现突变，但在CYP 11B 2基因中发现两个候选突变，R181 W和V386 A。当这些突变分别引入CYP 11B 2 cDNA和表达在培养的细胞中，R181 W减少18-羟化酶和废除18-氧化酶的活动，但留下11-β-羟化酶的活动完整，而V386 A引起一个小的，但一致的减少18-羟皮质酮的生产。所有受CMO-II缺陷影响的个体均为两种突变的纯合子，而8名无症状受试者仅为R181 W纯合子，3名仅为V386 A纯合子。这些研究结果证实，P450 XIB 2是介导肾上腺中18位氧化的主要酶，并表明在体外测定中检测不到的少量残余活性足以合成正常量的醛固酮。
Corticosterone methyloxidase II (CMO-II) deficiency is an autosomal recessive disorder of aldosterone biosynthesis, characterized by an elevated ratio of 18-hydroxycorticosterone to aldosterone in serum. It is genetically linked to the CYP11B1 and CYP11B2 genes that, respectively, encode two cytochrome P450 isozymes, P450XIB1 and P450XIB2. Whereas P450XIB1 only catalyzes hydroxylation at position 11-beta of 11-deoxycorticosterone and 11-deoxycortisol, P450XIB2 catalyzes the synthesis of aldosterone from deoxycorticosterone, a process that successively requires hydroxylation at positions 11-beta and 18 and oxidation at position 18. To determine the molecular genetic basis of CMO-II deficiency, seven kindreds of Iranian-jewish origin were studied in which members suffered from CMO-II deficiency. No mutations were found in the CYP11B1 genes, but two candidate mutations, R181W and V386A, were found in the CYP11B2 genes. When these mutations were individually introduced into CYP11B2 cDNA and expressed in cultured cells, R181W reduced 18-hydroxylase and abolished 18-oxidase activities but left 11-beta-hydroxylase activity intact, whereas V386A caused a small but consistent reduction in the production of 18-hydroxycorticosterone. All individuals affected with CMO-II deficiency were homozygous for both mutations, whereas eight asymptomatic subjects were homozygous for R181W alone and three were homozygous for V386A alone. These findings confirm that P450XIB2 is the major enzyme mediating oxidation at position 18 in the adrenal and suggest that a small amount of residual activity undetectable in in vitro assays is sufficient to synthesize normal amounts of aldosterone.