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Congenital adrenal hyperplasia is one of the most frequently inherited diseases. It is characterized by a severe decline in cortisol secretion, which results in a compensatory increase in ACTH and consequent adrenal growth (hyperplasia). Here we describe the first case of 11beta-hydroxylase deficiency that is caused by an unequal cross-over of the genes encoding aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1). CYP11B1 and CYP11B2 are located on chromosome 8q24 approximately 45 kb apart from each other. The investigated genetic recombination deleted the normal alleles of the two genes and created a chimeric fusion gene, which consists of the promotor and exons 1 through 4 of the aldosterone synthase gene plus intron 4 through exon 9 of the 11beta-hydroxylase gene. This recombination event subordinates any remaining 11beta-hydroxylase activity of the chimeric enzyme to the control mechanisms of CYP11B2, the expression of which is mainly regulated by angiotensin II and K(+). Normally the 11beta-hydroxylase activity is controlled by ACTH. The existence of the CYP11B2/CYP11B1 chimera was discovered by means of a PCR method and was confirmed with a Southern blot. Furthermore, by applying a minigene expression method we demonstrated a point mutation in intron 3 (IVS3+16G-->T) of the patient's second 11beta-hydroxylase allele that radically diminishes proper splicing of the pre-mRNA by giving rise to a new, highly preferred donor splice site.
Hampf et al. (2001) studied this question.