The chimeric gene linked to glucocorticoid-suppressible hyperaldosteronism encodes a fused P-450 protein prssessing aldosterone synthase activity

Abstract

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 11β and P-450 C18, 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 11β (encoded by exons 1–4 of CYP11B1) and the carboxyl-terminal side of P-450 C18 (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.