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

## TL;DR

A genetic mutation in IKBKB disrupts immune signaling and causes multiple immune-related diseases.

## Contribution

A novel splice-site variant in IKBKB is linked to multiple immune-mediated disorders via loss-of-function.

## Key findings

- A heterozygous splice-site variant in IKBKB leads to a truncated IKKβ protein.
- The mutant protein shows significantly reduced NF-κB activity and gene expression.
- The mutation decreases levels of p105 and p50, key NF-κB regulators.

## Abstract

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.