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URL of this page: https://medlineplus.gov/genetics/gene/ikbkg/

IKBKG gene

inhibitor of nuclear factor kappa B kinase regulatory subunit gamma

Normal Function

The IKBKG gene provides instructions for producing one piece (subunit) of the IKK protein complex, which is a group of related proteins that regulates the activity of nuclear factor-kappa-B. Nuclear factor-kappa-B is a protein complex that binds to DNA and controls the activity of other genes. 

When the IKK protein complex is in the resting state (inactive), nuclear factor-kappa-B and the IKK complex are attached (bound) together. In response to certain chemical signals, the IKK complex releases nuclear factor-kappa-B.

The IKBKG protein plays a regulatory role in the IKK complex. Once the IKBKG protein is turned on (activated), it activates the other proteins in the complex, which in turn releases nuclear factor-kappa-B. The loose nuclear factor-kappa-B then moves into the nucleus of the cell 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. Nuclear factor-kappa-B also appears to play a role in the signaling pathway that is critical for the formation of ectodermal tissues, including the skin, hair, teeth, and sweat glands. In addition, it protects the cell from certain signals that would otherwise cause it to self-destruct (undergo apoptosis).

Health Conditions Related to Genetic Changes

Anhidrotic ectodermal dysplasia with immune deficiency

Variants (also called mutations) in the IKBKG gene have been found to cause anhidrotic ectodermal dysplasia with immune deficiency (EDA-ID). EDA-ID is a condition characterized by the abnormal development of ectodermal tissues. In addition, people with EDA-ID often get infections because their immune system does not function well.

The IKBKG gene variants that cause EDA-ID impair the function of the IKBKG protein but do not completely eliminate its ability to regulate nuclear factor-kappa-B. These changes disrupt certain signaling pathways within immune cells and the cells that form ectodermal tissues. This impairs the immune system and disrupts the development of ectodermal tissues.

The severity of the signs and symptoms of EDA-ID depends on the amount of functional IKBKG protein the person has. People with more functional protein typically have milder forms of the disease.

Some people with EDA-ID have unusually dense bones (osteopetrosis) and swelling of soft tissues (lymphedema). This is sometimes referred to as OL-EDA-ID; the acronym is derived from each of the major features of the disorder. It is unclear how variants in the IKBKG gene contribute to osteopetrosis and lymphedema in people with OL-EDA-ID.

More About This Health Condition

Incontinentia pigmenti

Variants in the IKBKG gene have been identified in people with incontinentia pigmenti, a condition characterized by skin, tooth, and nail abnormalities and an increased risk of stroke and vision loss. 

The most common IKBKG gene variant that causes incontinentia pigmenti is a complex rearrangement that deletes some genetic material from the IKBKG gene. This change accounts for more than 60 to 80 percent of all cases of the condition. This change probably leads to the production of an abnormally small, nonfunctional version of the IKBKG protein.  

Other IKBKG gene variants that cause incontinentia pigmenti 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.

More About This Health Condition

Other disorders

IKBKG gene variants can cause 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. One type of mycobacterium causes tuberculosis, a respiratory disease that can be serious or life-threatening. Some mycobacterial infections are described as "opportunistic" because they do not cause illness in people with a normal immune system.  

The IKBKG gene variants associated with X-linked susceptibility to mycobacterial disease change the structure of the IKBKG protein. The altered protein disrupts certain signaling pathways within immune cells. As a result, people with this condition often have fewer immune cells, or they may have immune system cells that function poorly. These cells cannot defend the body effectively against mycobacterial infections. Due to these immune issues, people with X-linked susceptibility to mycobacterial disease often require treatment to restore immune function in order to resist infection and keep inactive (latent) infections suppressed. 

Because the IKBKG gene is on the X chromosome, which is one of the two sex chromosomes, individuals with one X chromosome (typical for males) who have a variant in their only copy of the gene can develop the condition. In people who have two X chromosomes (typical for females), a variant would have to occur in both copies of the IKBKG gene to cause the disorder.


Other Names for This Gene

  • FIP-3
  • FIP3
  • Fip3p
  • IKK-gamma
  • IP2
  • NEMO
  • NEMO_HUMAN
  • NF-kappa-B essential modulator
  • ZC2HC9

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Aradhya S, Woffendin H, Jakins T, Bardaro T, Esposito T, Smahi A, Shaw C, Levy M, Munnich A, D'Urso M, Lewis RA, Kenwrick S, Nelson DL. A recurrent deletion in the ubiquitously expressed NEMO (IKK-gamma) gene accounts for the vast majority of incontinentia pigmenti mutations. Hum Mol Genet. 2001 Sep 15;10(19):2171-9. doi: 10.1093/hmg/10.19.2171. Citation on PubMed
  • Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol. 2002 Aug;47(2):169-87; quiz 188-90. doi: 10.1067/mjd.2002.125949. Citation on PubMed
  • Bruckner AL. Incontinentia pigmenti: a window to the role of NF-kappaB function. Semin Cutan Med Surg. 2004 Jun;23(2):116-24. doi: 10.1016/j.sder.2004.01.005. Citation on PubMed
  • Bustamante J, Picard C, Boisson-Dupuis S, Abel L, Casanova JL. Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases. Ann N Y Acad Sci. 2011 Dec;1246:92-101. doi: 10.1111/j.1749-6632.2011.06273.x. Citation on PubMed or Free article on PubMed Central
  • Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, Bodemer C, Kenwrick S, Dupuis-Girod S, Blanche S, Wood P, Rabia SH, Headon DJ, Overbeek PA, Le Deist F, Holland SM, Belani K, Kumararatne DS, Fischer A, Shapiro R, Conley ME, Reimund E, Kalhoff H, Abinun M, Munnich A, Israel A, Courtois G, Casanova JL. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet. 2001 Mar;27(3):277-85. doi: 10.1038/85837. Citation on PubMed
  • Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, Frucht DM, Christel K, von Bernuth H, Jouanguy E, Feinberg J, Durandy A, Senechal B, Chapgier A, Vogt G, de Beaucoudrey L, Fieschi C, Picard C, Garfa M, Chemli J, Bejaoui M, Tsolia MN, Kutukculer N, Plebani A, Notarangelo L, Bodemer C, Geissmann F, Israel A, Veron M, Knackstedt M, Barbouche R, Abel L, Magdorf K, Gendrel D, Agou F, Holland SM, Casanova JL. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med. 2006 Jul 10;203(7):1745-59. doi: 10.1084/jem.20060085. Epub 2006 Jul 3. Citation on PubMed or Free article on PubMed Central
  • Fusco F, Bardaro T, Fimiani G, Mercadante V, Miano MG, Falco G, Israel A, Courtois G, D'Urso M, Ursini MV. Molecular analysis of the genetic defect in a large cohort of IP patients and identification of novel NEMO mutations interfering with NF-kappaB activation. Hum Mol Genet. 2004 Aug 15;13(16):1763-73. doi: 10.1093/hmg/ddh192. Epub 2004 Jun 30. Citation on PubMed
  • Heller S, Kolsch U, Magg T, Kruger R, Scheuern A, Schneider H, Eichinger A, Wahn V, Unterwalder N, Lorenz M, Schwarz K, Meisel C, Schulz A, Hauck F, von Bernuth H. T Cell Impairment Is Predictive for a Severe Clinical Course in NEMO Deficiency. J Clin Immunol. 2020 Apr;40(3):421-434. doi: 10.1007/s10875-019-00728-y. Epub 2020 Jan 21. Citation on PubMed
  • Scheuerle AE, Ursini MV. Incontinentia Pigmenti. 1999 Jun 8 [updated 2017 Dec 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1472/ Citation on PubMed
  • Shifera AS. The zinc finger domain of IKKgamma (NEMO) protein in health and disease. J Cell Mol Med. 2010 Oct;14(10):2404-14. doi: 10.1111/j.1582-4934.2010.01054.x. Citation on PubMed or Free article on PubMed Central
  • Smahi A, Courtois G, Rabia SH, Doffinger R, Bodemer C, Munnich A, Casanova JL, Israel A. The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Hum Mol Genet. 2002 Oct 1;11(20):2371-5. doi: 10.1093/hmg/11.20.2371. Citation on PubMed
  • Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, Israel A, Heiss NS, Klauck SM, Kioschis P, Wiemann S, Poustka A, Esposito T, Bardaro T, Gianfrancesco F, Ciccodicola A, D'Urso M, Woffendin H, Jakins T, Donnai D, Stewart H, Kenwrick SJ, Aradhya S, Yamagata T, Levy M, Lewis RA, Nelson DL. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000 May 25;405(6785):466-72. doi: 10.1038/35013114. Citation on PubMed
  • Temmerman ST, Ma CA, Zhao Y, Keenan J, Aksentijevich I, Fessler M, Brown MR, Knutsen A, Shapiro R, Jain A. Defective nuclear IKKalpha function in patients with ectodermal dysplasia with immune deficiency. J Clin Invest. 2012 Jan;122(1):315-26. doi: 10.1172/JCI42534. Epub 2011 Dec 12. Citation on PubMed or Free article on PubMed Central
  • Uzel G. The range of defects associated with nuclear factor kappaB essential modulator. Curr Opin Allergy Clin Immunol. 2005 Dec;5(6):513-8. doi: 10.1097/01.all.0000191241.66373.74. Citation on PubMed
  • Verma UN, Yamamoto Y, Prajapati S, Gaynor RB. Nuclear role of I kappa B Kinase-gamma/NF-kappa B essential modulator (IKK gamma/NEMO) in NF-kappa B-dependent gene expression. J Biol Chem. 2004 Jan 30;279(5):3509-15. doi: 10.1074/jbc.M309300200. Epub 2003 Nov 3. Citation on PubMed

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