278 : Inflammatory disease and an impaired type I interferon response resulting from a de novo human NEMO hypomorphic mutation
Toll-like receptor 3 and the RIG-I-like family of receptors (RLRs) mediate antiviral signaling through NEMO-dependent activation of transcription factors NF-κB and IRF3, which are recognized for their roles in inflammation and the induction of type I interferon. We identified an individual with Ectodermal Dysplasia, a history of in utero cytomegalovirus exposure, and persistent inflammatory disease. Sanger sequencing revealed a de novo synonymous mutation in IKBKG, which encodes NEMO, the NF-κB essential modulator. The mutation results in an mRNA splicing defect which leads to the production of a mutant protein containing an in-frame deletion of 51 residues, lacking a previously identified TANK (TRAF family member-associated NFKB activator) interaction domain. Co-immunoprecipitation studies revealed that the mutant form of NEMO from patient T cells is unable to recruit the IRF3 kinase TANK-binding kinase-1 (TBK1), due to impaired association with TANK. Patient fibroblasts stimulated with the RLR ligand poly (I:C) led to impaired induction of IRF3 response genes IFNB1, CCL5, CXCL10, IP10, OASL, and DDX58. Consequently, dermal fibroblasts infected with RSV or hPIV3 demonstrated increased virus propagation relative to healthy control cells. Impaired gene expression occurred despite enhanced nuclear translocation of IRF3, suggesting that the mechanism of impaired activation is not a simple defect in nuclear locof the transcription factor. In contrast to the impaired type I IFN response, canonical IKK activation and gene induction in dermal fibroblasts appeared relatively normal following TNF treatment. These results illustrate a novel mechanism of autoinflammatory disease due to aberrant expression of an alternately spliced NEMO and deficient IRF3-mediated response.