GENETIC-RECOMBINATION AS A CAUSE OF INHERITED DISORDERS OF ALDOSTERONE AND CORTISOL BIOSYNTHESIS AND A CONTRIBUTOR TO GENETIC-VARIATION IN BLOOD-PRESSURE

CYP11B1 (11 beta-hydroxylase) and CYP11B2 (aldosterone synthase) are s teroidogenic enzymes which mediate the final step (11 beta-hydroxylati on) in cortisol synthesis and the final three steps (11 beta-hydroxyla tion, 18-hydroxylation, and 18-oxidation) in aldosterone synthesis, re spectively. The enzymes share 93% identity in amino acid sequence and are encoded by two structurally similar genes which are located in tan dem on chromosome 8q22, approximately 40 kb apart. Expression of the a ldosterone synthase gene (CYP11B2) is limited to the zona glomerulosa of the adrenal cortex, thereby limiting the synthesis of aldosterone t o that zone, where it is principally regulated by plasma levels of ang iotensin II and potassium. The 11 beta-hydroxylase gene (CYP11B1) is e xpressed in the zona fasciculata, the zone which also expresses a 17-h ydroxylase activity, where it mediates cortisol synthesis under the co ntrol of ACTH. Genetic recombination involving a mispairing of the two CYP11B genes can lead to duplications and deletions of the genes, cre ation of hybrid genes of several forms, or transfer of coding and regu latory sequences from one gene to the other. Since the two genes have related bur different activities, are normally expressed in different zones, and respond to different physiological signals, such recombinat ion has the potential to generate a variety of inherited disorders of steroid production. In this paper we review the range of mutations whi ch can occur and the resulting disorders of steroid biosynthesis, and suggest some novel mutations which might be sought in variants of thes e endocrinological syndromes.