Mutations in steroid 21-hydroxylase (CYP21).

The inherited inability to synthesize cortisol is termed congenital adrenal hyperplasia. More than 90% of cases are caused by 21-hydroxylase deficiency. This syndrome is characterized by signs of androgen excess and often mineralocorticoid deficiency. Steroid 21-hydroxylase (P450c21) is a microsomal enzyme expressed in the adrenal gland that catalyzes conversion of 17-hydroxyprogesterone and progesterone to 11-deoxycortisol and deoxycorticosterone respectively. In man, this enzyme is encoded by the CYP21 (CYP21B) gene which is located in the HLA major histocompatibility complex along with a pseudogene, CYP21P (CYP21A). Mutations in CYP21 causing congenital adrenal hyperplasia are almost all generated by recombinations between CYP21 and CYP21P. These recombinations either delete CYP21 or transfer deleterious mutations from CYP21P to CYP21, a process termed apparent gene conversion. The degree of enzymatic compromise caused by each mutation is correlated with the clinical severity of the deficiency observed in patients carrying that mutation.