Miyahara K, Kawamoto T, Mitsuuchi Y, Toda K, Imura H, Gordon R D, Shizuta Y
Department of Medical Chemistry, Kochi Medical School, Japan.
Biochem Biophys Res Commun. 1992 Dec 15;189(2):885-91. doi: 10.1016/0006-291x(92)92286-7.
Glucocorticoid-suppressible hyperaldosteronism (GSH) is one variety of primary aldosteronism with hypertension and is inherited in an autosomal dominant mode. A recent report has indicated that GSH is caused by a gene duplication arising from unequal crossing over between the two genes, CYP11B1 and CYP11B2, encoding P-450(11 beta) and P-450C18, respectively (Lifton et al. Nature (1992) 355, 262-265). The nucleotide sequence analysis in the present study has demonstrated that unequal crossing over in the chimeric gene formed by the gene duplication occurs within the region from the 3'-portion of exon 4 through the 5'-portion of intron 4 in Australian GSH patients. Namely, the chimeric gene encodes a fused P-450 protein consisting of the amino-terminal side of P-450(11 beta) (encoded by exons 1-4 of CYP11B1) and the carboxyl-terminal side of P-450C18 (encoded by exons 5-9 of CYP11B2). When a cDNA corresponding to the chimeric gene is transfected into COS-7 cells, the fused P-450 protein expressed in the mitochondria exhibits steroid 18-hydroxylase or aldosterone synthase activity. These results provide the molecular genetic basis for the characteristic biochemical phenotype of GSH patients.
糖皮质激素可抑制性醛固酮增多症（GSH）是原发性醛固酮增多症伴高血压的一种类型，呈常染色体显性遗传。最近的一份报告指出，GSH是由两个分别编码P - 450(11β)和P - 450C18的基因CYP11B1和CYP11B2之间不等交换导致的基因重复引起的（Lifton等人，《自然》（1992年）355卷，262 - 265页）。本研究中的核苷酸序列分析表明，在澳大利亚GSH患者中，由基因重复形成的嵌合基因中的不等交换发生在从外显子4的3'端到内含子4的5'端的区域内。也就是说，嵌合基因编码一种融合的P - 450蛋白，该蛋白由P - 450(11β)的氨基端（由CYP11B1的外显子1 - 4编码）和P - 450C18的羧基端（由CYP11B2的外显子5 - 9编码）组成。当将与嵌合基因对应的cDNA转染到COS - 7细胞中时，在线粒体中表达的融合P - 450蛋白表现出类固醇18 - 羟化酶或醛固酮合酶活性。这些结果为GSH患者特征性的生化表型提供了分子遗传学基础。
