Steroid 11 beta-hydroxylase is encoded by two homologous genes,
CYP11B1 and
CYP11B2, located on chromosome 8q21-22.
CYP11B1 encodes a specific
cytochrome P-450 (P-450c11) necessary for
cortisol biosynthesis, with predominantly
11 beta-hydroxylase and moderate 18-hydroxylase activity, whereas
CYP11B2 encodes another
isozyme (P-450cmo) necessary for
aldosterone biosynthesis, with
11 beta-hydroxylase, 18-hydroxylase and 18-oxidase activities (the latter two termed
corticosterone methyl-oxidase I and II;
CMO-I and II, respectively). Two
steroid biosynthetic defects, both relatively frequent in Israel, are caused by specific mutations in each of these genes.
11 beta-Hydroxylase deficiency is frequent among Jews from Morocco (1 in 5000 to 7000 births), and is characterized by
virilization,
hypertension, impaired
cortisol biosynthesis, and increased
deoxycorticosterone and
androgens. Affected individuals have a single base substitution in exon 8 of
CYP11B1,
codon 448, from CGC (
arginine) to CAC (
histidine). This sequence, normally absent in
CYP11B2, constitutes a true point mutation within the
heme binding domain of
CYP11B1 that results in marked impairment of enzymatic activity. The clinical expression is characterized by a wide range of variability in the signs of both
androgen and
mineralocorticoid excess, even though an identical mutation was found in all but one of the affected alleles examined.
CMO-II deficiency is frequent among Jews from Iran (1 in 4000 births), and is characterized by a typical
salt-
wasting syndrome, increased
18-hydroxycorticosterone, impaired
aldosterone biosynthesis, and a high ratio of these
steroids. No mutation was found in
CYP11B1, but all individuals affected were homozygous for two missense mutations in
CYP11B2. The first, in exon 3,
codon 181, from CGG (
arginine) to TGG (tryptophane) is a mutation that completely abolishes both
CMO-I and II activities, whereas the second, in exon 7,
codon 386, from GTG (
valine) to GCG (
alanine) is a more conservative substitution that produces only a minimal reduction in
CMO-I activity. Individuals homozygous for either one of these mutations are asymptomatic.