Defective Function of Inhibitor of κB Kinase Subunit Beta Associated With Multiple Immune‐Mediated Disorders

Abnormal NF-κB activity has been previously implicated in a range of immune-mediated disorders. Here, we aimed to elucidate the genetic basis underlying the co-occurrence of vitiligo, Addison's disease and granuloma annulare in a 43-year-old woman. Whole-exome sequencing identified a heterozygous splice-site variant (c.1364+1G>A, p.Met455fsTer1) in IKBKB, encoding the Inhibitor of κB kinase subunit beta (IKKβ), predicted to result in a premature stop codon. Immunoblotting of keratinocytes transfected with the mutant construct demonstrated the presence of a truncated form of IKKβ. Using a luciferase reporter assay under the control of NF-κB-responsive element, we demonstrated significantly reduced activity of the mutant protein compared to wild-type, supporting a loss-of-function mechanism. In line with this observation, the mutant protein was found to result in decreased expression levels of genes known to be regulated by NF-κB. Furthermore, HeLa cells transfected with the p.Met455fsTer1 variant or IKBKB-targeted siRNA exhibited markedly reduced levels of p105 and its processed form p50, compared with HeLa cells transfected with wild-type IKBKB or control siRNA, respectively. Collectively, these findings indicate that a loss-of-function effect in IKBKB may underlie the co-occurrence of a number of immune-mediated disorders through disruption of NF-κB signalling.