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 (P450C18), or
aldosterone synthase (P450aldo), 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 P450C18 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 (Arg181-->Trp) in exon 3 and GTG-->GCG (Val386-->Ala) in exon 7.
CYP11B1, the gene for
steroid 11 beta-hydroxylase (P45011 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 P450C18 whereas
CMO II deficient patients are leaky mutants with an altered P450C18 activity.(ABSTRACT TRUNCATED AT 250 WORDS)