Impact of Genome Complexity of the CYP21A2 Gene on Adrenal Steroidogenesis

Steroidogenesis in the adrenal cortex generates mineralocorticoids, glucocorticoids, and androgens, all of which are mediated by numerous enzymes and regulatory factors from the precursor, cholesterol. Defective adrenal steroidogenesis disorders include Addison's disease, congenital adrenal hyperplasia (CAH), and Cushing syndrome. CAH is one of the most common inborn errors of metabolism, causing impaired adrenal cortisol and aldosterone production with increased androgen secretion. P450c21-hydroxylase deficiency caused by inactivating mutations in the 21-hydroxylase gene (CYP21A2) accounts for 95% of mutations in these CAH patients. Notably, pseudogene-derived CYP21A2 lesions including mutations or large rearrangements represent the majority of CAH alleles, and the combination of altered alleles reflects the phenotypic severity of CAH, either simple virilizing or salt-wasting classical form. In addition, gene copy number variation has been correlated to disease susceptibility at the post-genomic era. This article reviews the complex organization of the CYP21 locus and its possible impact on phenotypic expression in CAH patients, emphasizing the concept of haplotype variations for CAH patients.