Akademik Veri Yönetim Sistemi
NATURE COMMUNICATIONS, cilt.15, sa.1, 2024 (SCI-Expanded, Scopus)
IKK alpha 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 IKK alpha 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 IKK alpha, which is present in three children from two Turkish families. This variant, referred to as IKK alpha 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, IKK alpha G167R abolishes the kinase activity of IKK alpha, leading to impaired activation of the non-canonical NF-kappa B pathway. Patients carrying IKK alpha 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 IKK alpha variant that results in early embryonic lethality in humans, the deficiency of IKK alpha's kinase activity is compatible with human life. However, it significantly disrupts the homeostasis of the immune system, underscoring the essential and non-redundant kinase function of IKK alpha in humans. IKK alpha is an essential regulator of the noncanonical NF-kappa B signalling, lack of which is incompatible with life. Here authors show that a homozygous missense variant in humans, G167R, disrupting its kinase activity upstream of the non-canonical NF-kappa B pathway, leads to disrupted innate and adaptive immune functions while largely sparing other major organ systems.