Inborn errors of aldosterone biosynthesis in humans

• Published in: Steroids 1995, Vol.60 (1), p.15-21
• Main Authors: Shizuta, Yutaka, Kawamoto, Takeshi, Mitsuuchi, Yasuhiro, Miyahara, Kaoru, Rösler, Ariel, Ulick, Stanley, Imura, Hiroo
• Format: Article
• Language: English
• Subjects: Adrenal Hyperplasia, Congenital; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Aldosterone - biosynthesis; aldosterone synthesis; Amino Acid Sequence; Base Sequence; Biological and medical sciences; CMO I; CMO II; Cytochrome P-450 CYP11B2; Cytochrome P-450 Enzyme System - deficiency; Endocrinopathies; Humans; inherited diseases; Medical sciences; Metabolism, Inborn Errors - genetics; Mixed Function Oxygenases - deficiency; Molecular Sequence Data; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; P450 11β; P450 C18
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/0039-128X(94)00023-6

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 G TG → G CG (Val 386 → Ala) in exon 7. CYP11B1, the gene for steroid 11β-hydroxylase (P450 11β) 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