Corticosterone methyloxidase II (
CMO-II) deficiency is an autosomal recessive disorder of
aldosterone biosynthesis, characterized by an elevated ratio of
18-hydroxycorticosterone to
aldosterone in serum. It is genetically linked to the
CYP11B1 and
CYP11B2 genes that, respectively, encode two
cytochrome P450 isozymes, P450XIB1 and P450XIB2. Whereas P450XIB1 only catalyzes hydroxylation at position 11 beta of 11-deoxycorticosterone and
11-deoxycortisol, P450XIB2 catalyzes the synthesis of
aldosterone from
deoxycorticosterone, a process that successively requires hydroxylation at positions 11 beta and 18 and oxidation at position 18. To determine the molecular genetic basis of
CMO-II deficiency, seven kindreds of Iranian-Jewish origin were studied in which members suffered from
CMO-II deficiency. No mutations were found in the
CYP11B1 genes, but two candidate mutations, R181W and V386A, were found in the
CYP11B2 genes. When these mutations were individually introduced into
CYP11B2 cDNA and expressed in cultured cells, R181W reduced 18-hydroxylase and abolished 18-oxidase activities but left
11 beta-hydroxylase activity intact, whereas V386A caused a small but consistent reduction in the production of
18-hydroxycorticosterone. All individuals affected with
CMO-II deficiency were homozygous for both mutations, whereas eight asymptomatic subjects were homozygous for R181W alone and three were homozygous for V386A alone. These findings confirm that P450XIB2 is the major
enzyme mediating oxidation at position 18 in the adrenal and suggest that a small amount of residual activity undetectable in in vitro assays is sufficient to synthesize normal amounts of
aldosterone.