Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

Abstract

Communicated by Andrew O.M. WilkieMutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 chromosomal region, encodes for the regulatory subunit of the inhibitor of kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kB pathway. Therefore, the remarkably heterogeneous and often severe clinical presentation reported in IP is due to the pleiotropic role of this signaling transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG rearrangement found in IP females (which is lethal in males), a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work. The updated distribution of all the IP-and EDA-ID-causing mutations along the IKBKG gene highlights a secondary hotspot mutation in exon 10, which contains only 11% of the protein. Furthermore, familial inheritance analysis revealed an unexpectedly high incidence of sporadic cases (465%). The sum of the observations can aid both in determining the molecular basis of IP and EDA-ID allelic diseases, and in genetic counseling in affected families. Hum Mutat 29(5), [595][596][597][598][599][600][601][602][603][604] 2008.

The IKK Complex, a Central Regulator of NF- B Activation

“…The mutations affecting NEMO interfere with both the EDA/EDAR cascade and the NF-kB-dependent pathways involved in the innate and acquired immune response. Mutations leading to EDA-ID have been shown to cover the entire NEMO coding region, and are essentially missense mutations and small deletions (Fusco et al 2008;Hanson et al 2008). Some patients carrying NEMO mutations show infectious susceptibility to specific pathogens, whereas others associate EDA-ID with osteopetrosis and lymphedema.…”

Kaposi's Sarcoma-Associated Herpesvirus vFLIP and Human T Cell Lymphotropic Virus Type 1 Tax Oncogenic Proteins Activate IκB Kinase Subunit γ by Different Mechanisms Independent of the Physiological Cytokine-Induced Pathways

“…Like cytokine activation via the ubiquitin binding region of IKK␥, Tax activation of IKK is inhibited by a K277E mutation within the coiled coil, which may block a conformational change induced by binding Tax or ubiquitin and required for activation. Mutation of IKK␥ residue L227P is associated with a rare functional deficiency of IKK␥ in anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (7). This mutation has a destabilizing effect, rendering the recombinant protein susceptible to proteolysis (1).…”

The Zinc Finger of NEMO Is a Functional Ubiquitin-binding Domain

“…This distinct pathway is activated by UV radiation and other DNA-damaging agents and involves import of NEMO into the nucleus, where it interacts with the ataxia telangiectasia mutated (ATM) checkpoint kinase. The importance of NEMO ZF is also emphasized by the fact that (i) several mutations in the ZF are linked to the human diseases, anhidrotic ectodermal dysplasia with immunodeficiency and incontinentia pigmenti (19), and that (ii) mice lacking the NEMO ZF die during embryonic development (20).…”