The chimeric gene linked to glucocorticoid-suppressible hyperaldosteronism encodes a fused P-450 protein possessing aldosterone synthase activity.
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.
Miyahara
K
K
Department of Medical Chemistry, Kochi Medical School, Japan.
Kawamoto
T
T
Mitsuuchi
Y
Y
Toda
K
K
Imura
H
H
Gordon
R D
RD
Shizuta
Y
Y
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002678:Chimera; D019405:Cytochrome P-450 CYP11B2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D005796:Genes; D006801:Humans; D006929:Hyperaldosteronism / Q000201:enzymology / Q000235:genetics*; D007438:Introns; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family; D009838:Oligodeoxyribonucleotides; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D009838:Oligodeoxyribonucleotides; D011993:Recombinant Fusion Proteins; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase