IKBKG

The IKBKG gene (also known as NEMO) provides instructions for making a protein that plays a critical role in regulating nuclear factor-kappa-B. Nuclear factor-kappa-B is a group of related proteins (a protein complex) that binds to DNA and controls the activity of other genes.

Within cells, the IKBKG protein interacts with two enzymes, IKK-alpha and IKK-beta, to activate nuclear factor-kappa-B. The activated factor then moves into the nucleus and binds to DNA. Nuclear factor-kappa-B regulates the activity of multiple genes, including genes that control the body's immune responses and inflammatory reactions. It also protects the cell from certain signals that would otherwise cause it to self-destruct (undergo apoptosis).

incontinentia pigmenti - caused by mutations in the IKBKG gene

More than 30 mutations in the IKBKG gene have been identified in people with incontinentia pigmenti. The most common mutation, a complex rearrangement that deletes some genetic material from the IKBKG gene, accounts for more than 80 percent of all cases of the condition. This mutation probably leads to the production of an abnormally small, nonfunctional version of the IKBKG protein. Other people with incontinentia pigmenti have mutations that prevent the production of any IKBKG protein. Without this protein, nuclear factor-kappa-B cannot be activated. Cells without active nuclear factor-kappa-B are more sensitive to signals that trigger them to self-destruct. The resulting abnormal cell death likely leads to the signs and symptoms of incontinentia pigmenti.

osteopetrosis - caused by mutations in the IKBKG gene

Several mutations in the IKBKG gene have been found to cause a rare form of osteopetrosis with an X-linked pattern of inheritance. Researchers often refer to this condition as OL-EDA-ID, an acronym derived from each of the major features of the disorder. In addition to the abnormally dense bones characteristic of osteopetrosis, OL-EDA-ID is associated with abnormal swelling caused by a buildup of fluid (lymphedema) and a condition called anhydrotic ectodermal dysplasia that affects the skin, hair, teeth, and sweat glands. Affected individuals also have a malfunctioning immune system (immunodeficiency), which allows severe, recurrent infections to develop.

The mutations responsible for OL-EDA-ID impair the normal function of the IKBKG protein, which reduces activation of nuclear factor-kappa-B. These changes disrupt certain signaling pathways within immune cells, resulting in immunodeficiency. It is unclear how IKBKG mutations lead to the other features of OL-EDA-ID, although the signs and symptoms are likely caused by abnormal nuclear factor-kappa-B signaling in other types of cells.

other disorders - caused by mutations in the IKBKG gene

Mutations in the IKBKG gene have also been identified in people, usually males, with other conditions affecting the skin, hair, teeth, and nails. These mutations reduce but do not eliminate the function of the IKBKG protein. For example, mutations in this gene have been shown to cause a disorder called hypohidrotic ectodermal dysplasia with immune deficiency (EDA-ID), which is characterized by missing or abnormal teeth, an inability to sweat, and recurrent serious infections.

IKBKG mutations also account for some cases of a condition known as X-linked susceptibility to mycobacterial disease. People with this condition have an increased risk of infection with forms of bacteria called mycobacteria. Some of these foreign invaders do not cause disease in healthy people but can cause lung disease and other medical problems in those with an increased susceptibility to infection. Another type of mycobacterium causes tuberculosis, a respiratory disease that can be serious or life-threatening. The IKBKG mutations responsible for X-linked susceptibility to mycobacterial disease alter the structure of the IKBKG protein. The defective protein disrupts certain signaling pathways within immune cells, which prevents the immune system from defending the body effectively against mycobacterial infection.