A database for immunodeficiency due to mutations in nuclear factor kappa B pathway genes
Abstract
Nuclear factor kappa B (NFκB) pathway defects are associated with immunodeficiency; however, multiple phenotypes for mutations in genes encoding for NFκB proteins have been reported. We sought to create a database of published mutations in the genes encoding for IKKα and IKKβ and the regulatory subunit IKKγ, also referred to as NFκB essential modulator (NEMO). All published mutations were reviewed. The clinical and laboratory phenotypes were recorded and yearly updates of new mutations and phenotypes will be performed. Multiple immunodeficiency and infectious phenotypes were recorded particularly for patients with NEMO gene mutations. Even patients with the same NEMO mutation tended to have somewhat different phenotypes. In patients with primary immunodeficiency, the clinical phenotype may not direct the clinician to the genetic cause of the disease. Therefore, a comprehensive database will expand our knowledge and enhance the clinician’s ability to predict which gene mutation is the cause of the immunodeficiency. This database can assist clinicians in the diagnoses of patients with specific features of immunodeficiency.
Statement of novelty: A comprehensive database of published mutations in the genes encoding for IKKα, IKKβ, and IKKγ was created. This database may aid the clinician in recognizing specific immunodeficiency phenotypes.
Introduction
The nuclear factor kappa B (NFκB) family of transcription factors is essential for a variety of biological functions including response to stress, infection, and inflammation. The NFκB is normally found in the cytoplasm due to the effects of the inhibitor of NFκB, (IkB). Upon canonical stimulation of the NFκB pathway, the IκB components are phosphorylated by the IκB kinase (IKK) which is composed of 2 catalytic subunits (IKKα and IKKβ) and a regulatory subunit (IKKγ, also referred to as NEMO, NFκB essential modulator, IKBKG), leading to the degradation of the IκB which allows for translocation of the NFκB into the nucleus and transcription of pro-inflammatory genes (Gilmore 2006).
As expected, mutations within this pathway have a deleterious effect on susceptibility to malignancies, development, and the immune system. Mutations in genes encoding for NEMO, IκKα, and IKKβ cause a wide variety of immunodeficiency phenotypes. The NEMO gene is found at the Xq28 region, males born with hypomorphic mutations in the NEMO gene usually suffer from combined immunodeficiency with or without ectodermal dysplasia. Null mutations in males are lethal in utero and female carriers of mutations in the NEMO gene have a typical skin condition with streaks of hyperpigmentation known as incontinenta pigmenti. Diseases from mutations in IκKα and IKKβ are inherited in an autosomal recessive manner (Courtois and Gilmore 2006). We have created a database (Tables 1–3) of published mutations in NEMO, IκKα, and IKKβ and we show a wide clinical spectrum of immunodeficiency and infectious phenotypes. This database can aid the clinician in recognizing specific immunodeficiency phenotypes and promote the diagnosis of NFκB pathway defects.
Table 1:
Table 2:
Table 3:
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LymphoSign Journal
Volume 3 • Number 4 • December 2016
Pages: 165 - 178
History
Received: 23 August 2016
Accepted: 10 November 2016
Accepted manuscript online: 14 November 2016
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© 2016.
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ArnonBroides. 2016. A database for immunodeficiency due to mutations in nuclear factor kappa B pathway genes. LymphoSign Journal.
3(4): 165-178. https://doi.org/10.14785/lymphosign-2016-0009
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