Genetic recombination as a cause of inherited disorders of aldosterone and cortisol biosynthesis and a contributor to genetic variation in blood pressure

Abstract

CYP11B1 (11 beta-hydroxylase) and CYP11B2 (aldosterone synthase) are steroidogenic enzymes which mediate the final step (11 beta-hydroxylation) in cortisol synthesis and the final three steps (11 beta-hydroxylation, 18-hydroxylation, and 18-oxidation) in aldosterone synthesis, respectively. The enzymes share 93% identity in amino acid sequence and are encoded by two structurally similar genes which are located in tandem on chromosome 8q22, approximately 40 kb apart. Expression of the aldosterone synthase gene (CYP11B2) is limited to the zona glomerulosa of the adrenal cortex, thereby limiting the synthesis of aldosterone to that zone, where it is principally regulated by plasma levels of angiotensin II and potassium. The 11 beta-hydroxylase gene (CYP11B1) is expressed in the zona fasciculata, the zone which also expresses a 17-hydroxylase activity, where it mediates cortisol synthesis under the control of ACTH. Genetic recombination involving a mispairing of the two CYP11B genes can lead to duplications and deletions of the genes, creation of hybrid genes of several forms, or transfer of coding and regulatory sequences from one gene to the other. Since the two genes have related but different activities, are normally expressed in different zones, and respond to different physiological signals, such recombination has the potential to generate a variety of inherited disorders of steroid production. In this paper we review the range of mutations which can occur and the resulting disorders of steroid biosynthesis, and suggest some novel mutations which might be sought in variants of these endocrinological syndromes.