Molecular genetics of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia results from a deficiency in any of the five enzymes necessary to synthesize cortisol from cholesterol: cholesterol desmolase (P450scc), 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17-hydroxylase (P450c17), 21-hydroxylase (P450c21) and 11-hydroxylase (P450c11). P450scc and P450c11 are structurally-related mitochondrial cytochrome P450 enzymes, whereas P450c17 and P450c21 are microsomal enzymes. The P450scc gene, CYP11A, is located on chromosome 15, and the P450c17 gene, CYP17, is on chromosome 10. The P450c21 gene, CYP21B, and a pseudogene, CYP21A, are located in the HLA major histocompatibility complex on chromosome 6p, while the P450c11 gene, CYP11B, is on chromosome 8q along with a second related gene of unknown function. Thus, despite common regulation by ACTH, there is no clustering of the genes for steroidogenic enzymes. CYP11A and CYP11B have an identical intron-exon organization, and CYP17 and CYP21B have similar gene structures, but the two pairs of genes encoding mitochondrial and microsomal P450 enzymes resemble each other poorly. More than 90% of cases of congenital adrenal hyperplasia result from 21-hydroxylase deficiency, and most of the remainder are caused by 11-hydroxylase deficiency. About one-quarter of 21-hydroxylase deficiency alleles are associated with a deletion of all or part of CYP21B. Most of the remaining mutant alleles result from transfers of deleterious mutations from the CYP21A pseudogene to CYP21B, a process termed gene conversion. These mechanisms provide an explanation for the relatively high frequency of 21-hydroxylase deficiency. The clinical severity of various forms of 21-hydroxylase deficiency may be roughly correlated with particular mutations.