Defective kinase activity of IKKa leads to combined immunodeficiency and disruption of immune tolerance in humans

IKKa is a multifunctional serine/threonine kinase that controls various biological processes, either dependent on or independent of its kinase activity. However, the importance of the kinase function of IKKa in human physiology remains unknown since no biallelic variants disrupting its kinase activity have been reported. In this study, we present a homozygous germline missense variant in the kinase domain of IKKa, which is present in three children from two Turkish families. This variant, referred to as IKKa G167R, is in the activation segment of the kinase domain and affects the conserved (DF/LG) motif responsible for coordinating magnesium atoms for ATP binding. As a result, IKKa G167R abolishes the kinase activity of IKKa, leading to impaired activation of the non-canonical NF-kB pathway. Patients carrying IKKa G167R exhibit a range of immune system abnormalities, including the absence of secondary lymphoid organs, hypogammaglobulinemia and limited diversity of T and B cell receptors with evidence of autoreactivity. Overall, our findings indicate that, unlike a nonsense IKKa variant that results in early embryonic lethality in humans, the deficiency of IKKa's kinase activity is compatible with human life. However, it significantly disrupts the homeostasis of the immune systems, underscoring the essential and non-redundant kinase function of IKKa in humans.