INBORN-ERRORS OF ALDOSTERONE BIOSYNTHESIS IN HUMANS

Corticosterone methyl oxidase (CMO) type I and type II deficiencies are inborn errors at the penultimate and ultimate steps in the biosynthesis of aldosterone in humans. Recently, steroid 18-hydroxylase (P450(C18)), or aldosterone synthase (P450(aldo)), was shown to be a multifunctional enzyme catalyzing these two steps of aldosterone biosynthesis, i.e., the conversion of corticosterone to 18-hydroxycorticosterone and the subsequent conversion of 18-hydroxycorticosterone to aldosterone. This observation suggests that CMO I and CMO II deficiencies are derived from two different mutations in the P450(C18) gene (CYP11B2). To elucidate whether or not this is the case, we performed molecular genetic studies on CYP11B2 of both types of patients. Nucleotide sequence analysis has indicated that the gene of CMO I deficient patients is completely inactivated by a frameshift to form a stop codon due to a 5-bp nucleotide deletion in exon 1. Sequence analysis of CYP11B2 of CMO II deficient patients has revealed two point mutations, CGG --> TGG (Arg(181) --> Trp) in exon 3 and GTG --> GCG (Val(386) --> Ala) in exon 7. CYP11B1, the gene for steroid 11 beta-hydroxylase (P450(11 beta)) which was previously postulated to be the target for CMO II deficiency, is not impaired in these two types of patients. Expression studies using the corresponding mutant cDNAs have shown that CMO I deficient patients are null mutants with a complete lack of P450(C18) whereas CMO II deficient patients are leaky mutants with an altered P450(C18) activity. These results provide molecular genetic evidence to show that CMO I and CMO II deficiencies are caused by two different mutations in the single gene, CYP11B2, coding for P450(C18), which plays a major role in the biosynthesis of aldosterone in humans.