Pannicke et al. (2013) identified a homozygous mutation in IKBKB encoding IκB kinase 2 (IKK2), resulting in a frameshift leading to a premature stop codon (pGln432Profs*62) in four patients with presenting with SCID. All the IKBKB LOF mutations published until today, resulted in a complete lack of IKK2 protein expression with or without decreased IKK complex expression.
Functional validation of a novel hypomorphic IKBKB mutation
In a boy with recurrent invasive bacterial infection, a private homozygous missense variant in IKBKB (c. 73G>A, p. G25R, CADD-score 29,5; predicted to be damaging in silico) was identified in a whole exome sequencing approach. Patient’s T- and B cells were almost exclusively of naïve phenotype. Hypogammaglobulinemia and polysaccharide antibody deficiency were observed.
The mutation results in normal IKK2 and normal IKK complex expression in different cell types. A significantly decreased IL-6 and IL-8 production after stimulation with LPS and flagellin was observed in patient’s fibroblasts. Moreover, the nuclear translocation of NF-κ p65 after stimulation with LPS was delayed and diminished in patient’s fibroblasts compared to control fibroblasts. Results of ultimate validation results are pending.
Hypomorphic mutations, that decrease but do not abolish the function of a gene product, can result in a milder phenotype or delayed onset of disease. Numerous examples can be found in PID related genes. Further investigation of the functional effects of the described IKBKB mutation will help deciphering the role of IKK2 in the NF-κB pathway.