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Abstract
The most potent corticosteroids are 11β-hydroxylated compounds. In humans, two cytochrome
P450 isoenzymes with 11β-hydroxylase activity, catalysing the biosynthesis of cortisol
and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11β-hydroxylase
(P450c11), is expressed on high levels in the zona fasciculata and is regulated by
ACTH. CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed
in the zona glomerulosa under primary control of the renin-angiotensin system. Aldosterone
synthase has 11β-hydroxylase activity as well as 18-hydroxylase activity and 18-oxidase
activity. The substrate for CYP11B2 is 11-deoxycorticosterone, that of CYP11B1 is
11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH)
due to 11β-hydroxylase deficiency. This disorder is characterized by androgen excess
and hypertension. Mutations in CYP11B2 cause congenital hypoaldosteronism (aldosterone
synthase deficiency) which is characterized by life-threatening salt loss, failure
to thrive, hyponatraemia and hyperkalaemia in early infancy. Both disorders have an
autosomal recessive inheritance. Classical and nonclassical forms of 11β-hydroxylase
deficiency can be distinguished. Studies in heterozygotes for classical 11β-hydroxylase
deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated
plasma levels of 11-deoxycortisol after ACTH stimulation). In infants with congenital
hypoaldosteronism, a comparable frequency of 18-hydroxylase deficiency (aldosterone
synthase deficiency type I) and of 18-oxidase deficiency (aldosterone synthase deficiency
type II) can be found. Molecular genetic studies of the CYP11B1 and CYP11B2 genes
in 11β-hydroxylase deficiency or aldosterone synthase deficiency have led to the identification
of several mutations. Transfection experiments showed loss of enzyme activity in vitro.
In some of the patients with 18-oxidase deficiency (aldosterone synthase deficiency
type II) no mutations in the CYP11B2 gene were identified. Refined methods for steroid
determination are the basis for the diagnosis of inborn errors of steroidogenesis.
Molecular genetic studies are complementary; on the one hand, they have practical
importance for the prenatal diagnosis of virilizing CAH forms and on the other hand,
they are of theoretical importance in terms of our understanding of the functioning
of cytochrome P450 enzymes.