CYP11B1

The CYP11B1 gene provides instructions for making an enzyme called 11-beta-hydroxylase. This enzyme is found in the adrenal glands, which are located on top of the kidneys. The 11-beta-hydroxylase enzyme is a member of the cytochrome P450 family of enzymes. These enzymes are involved in many processes in the body.

The 11-beta-hydroxylase enzyme helps produce hormones called cortisol and corticosterone. Specifically, the enzyme helps convert a molecule called 11-deoxycortisol to cortisol, and helps convert another molecule called 11-deoxycorticosterone to corticosterone. These processes are triggered by the release of a hormone called adrenal corticotrophic hormone (ACTH) by the pituitary gland, located at the base of the brain.

Cortisol helps maintain blood sugar levels, protects the body from stress, and suppresses inflammation. Corticosterone is converted to the hormone aldosterone by the aldosterone synthase enzyme, which is produced from the nearby CYP11B2 gene. Aldosterone helps control blood pressure by maintaining proper salt and fluid levels in the body.

congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency - caused by mutations in the CYP11B1 gene

More than 80 mutations in the CYP11B1 gene have been found to cause congenital adrenal hyperplasia (CAH) due to 11-beta-hydroxylase deficiency. 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 precursors that are used to form these hormones instead build up in the adrenal gland and are converted to androgens, which are the male sex hormones. 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 hypertension in individuals with the classic form of CAH due to 11-beta-hydroxylase deficiency.

familial hyperaldosteronism - caused by mutations in the CYP11B1 gene

The genetic change responsible for familial hyperaldosteronism type I fuses a section of the CYP11B1 gene with a section of the CYP11B2 gene. In this fused gene, a section of the CYP11B1 gene called a promoter region, which normally starts the production of the 11-beta-hydroxylase enzyme, is attached to the section of the CYP11B2 gene that provides instructions for making aldosterone synthase. In this position, the CYP11B1 promoter region, rather than starting production of 11-beta-hydroxylase, instead starts the production of aldosterone synthase from the CYP11B2 gene.

The activity of the CYP11B1 gene's promoter region is triggered by ACTH. As a result of the fused gene, aldosterone synthase activity is abnormally responsive to ACTH levels, resulting in excessive amounts of aldosterone being produced. The excessive aldosterone production leads to the high blood pressure (hypertension) associated with familial hyperaldosteronism type I.