Alt. symbols: IP2 | IP1 | IKK-gamma | NEMO | Fip3p | FIP-3 | FIP3 | ZC2HC9

Approved name: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma
Alt. names: incontinentia pigmenti, inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma, inhibitor of nuclear factor kappa B kinase subunit gamma

Location: Xq28: 154541199 - 154565046 (+)
Gene type: protein_coding, 22 transcripts.

Scores: LoFtool: | pLI: 0.62861452 | LOEUF: 1.373

HGNC: 5961

NCBI: 8517, RefSeq: NG_009896.1

Ensembl: ENSG00000269335.7

LRG_70 | Status: public

OMIM: 300248

Expression | ProteinAtlas

IKBKG encodes NEMO, the regulatory gamma subunit of the IKB kinase (IKK) complex, which it forms along with IKBKA and IKBKB. This complex leads to the proteolytic degradation of the NF-κB inhibitor IκBα, enabling the activated NF-κB transcription factor complex to translocate to the nucleus to regulate gene expression.

NEMO mutations are associated with a broad range of phenotypes, from copy number variants that lead to Incontinentia pigmenti [OMIM: 308300] in mostly females to hemizygous hypomorphic mutations that result in X-linked (EDA-ID) ectodermal dysplasia with anhidrosis (or hypohidrosis) and immunodeficiency [OMIM: 300291, 300636], affecting mostly males. Zilberman-Rudenko (2016) identified a distinct group of patients with NEMO C-terminal deletion (ΔCT-NEMO) mutations who develop inflammatory sk in and GI disease in addition to EDA-ID (PMID: 26802121). Both primary patient cells and reconstituted cell lines showed increased IκB kinase (IKK) activity and production of pro-inflammatory cytokines such as IL-1β and IL-6 in response to stimuli. Unlike previously described LOF mutations, these ΔCT-NEMO mutants were unable to recruit A20, a negative regulator of NF-κB activation, to the NEMO C-terminus, leading to increased and prolonged inappropriate NF-κB activation in response to TNF and TLR stimulation in both CD14+ monocytes and CD4+ T cells. More recently, de Jesus et al. (2020) identified 4 unrelated patients (3 males and 1 female) with NEMO-NDAS (NEMO-Deleted Exon 5 Autoinflammatory Syndrome), which results from distinct X-linked IKBKG mutations that lead to exon 5 skipping (NEMO-Δex5). These patients presented with very early onset signs of tissue- and organ-specific inflammation including fevers, panniculitis, and transaminitis that progressed to include hepatosplenomegaly and intracranial hemorrhage. They also showed some EDA-ID-like features such as conical teeth and hypogammaglobulinemia, but no clinical evidence of recurrent or severe infection susceptibility. Patients with NEMO-NDAS showed increased ISG expression, but 3 ISGs that are also NF-kB targets (CXCL10, GBP1 and SOCS1) were the main contributors to the IFN signature found in these patients (PMID: 31874111). Lee et al. (2022) recently demonstrated that the NEMO-NDAS isoform (NEMO-Δex5) is unable to associate with TBK1 (PMID: 35289316). Unlike patient skin fibroblasts, which showed reduced anti-viral immunity and inability to activate NF-κB in response to TLR3 or RIG-I–like receptor (RLR) stimulation, NEMO-Δex5-expressing monocytes, macrophages, and CD4+ T cells were responsive to poly(I:C) stimulation and showed increased type I IFN and NF-κB gene signatures, even though patients did not have classic type I IFNopathy features. Both immune cells and TNF-stimulated dermal fibroblasts were able to upregulate the inducible IKK complex (IKKi) that was then stabilized by NEMO-Δex5, promoting type I IFN induction and antiviral responses (PMID: 35289316). [Load More]