2.1 Congenital Adrenal Hyperplasia Due to 11-Beta-Hydroxylase Deficiency

More than 80 mutations in the CYP11B1 gene have been found to cause congenital adrenal hyperplasia (CAH) due to 11-beta-hydroxylase deficiency, a disorder in which the adrenal glands produce excess male sex hormones (androgens). Most of these mutations change single protein building blocks (amino acids) in the 11-beta-hydroxylase enzyme and decrease the function of the enzyme. CYP11B1 gene mutations that severely reduce or eliminate the function of the enzyme typically result in the classic form of CAH due to 11-beta-hydroxylase deficiency. Mutations that allow for some enzyme function usually result in the non-classic form of the disorder.

Some mutations that cause the classic form of CAH due to 11-beta-hydroxylase deficiency fuse sections of the CYP11B1 gene with sections of a nearby gene called CYP11B2. The added part of the CYP11B2 gene contains a section called a promoter region, which normally controls (regulates) production of the protein made by the CYP11B2 gene. As a result, the CYP11B1 gene is regulated by the CYP11B2 gene promoter region rather than its own promoter region. In addition, the fusion typically deletes parts of the CYP11B1 gene. These changes in the gene's regulation and structure diminish production of 11-beta-hydroxylase.

Both types of CAH due to 11-beta-hydroxylase deficiency interfere with the production of cortisol and corticosterone. The molecules that are used to form these hormones instead build up in the adrenal gland and are converted to androgens. The excess production of androgens leads to abnormalities of sexual development in people with CAH due to 11-beta-hydroxylase deficiency. A buildup of the molecule 11-deoxycorticosterone, the substance that 11-beta-hydroxylase converts to form corticosterone, increases salt retention, leading to high blood pressure (hypertension) in individuals with the classic form of CAH due to 11-beta-hydroxylase deficiency.

2.2 Familial Hyperaldosteronism

A genetic change affecting the CYP11B1 gene causes familial hyperaldosteronism type I, a disorder that leads to hypertension. This change joins (fuses) a section of the CYP11B1 gene called a promoter region, which normally helps start the production of the 11-beta-hydroxylase enzyme, to the section of the CYP11B2 gene that provides instructions for making aldosterone synthase.

By binding to the CYP11B1 gene's promoter region, ACTH normally triggers production of the 11-beta-hydroxylase enzyme. In the fusion gene, ACTH binding abnormally triggers production of aldosterone synthase. High levels of aldosterone synthase result in excessive aldosterone production, which leads to the hypertension associated with familial hyperaldosteronism type I.