Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia.
Department of Paediatric Immunology, Institute of Child Health, Hacettepe University, Ankara, Türkiye.
Nat Commun. 2024 Nov 16;15(1):9944. doi: 10.1038/s41467-024-54345-4.
IKKα 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 IKKα 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 IKKα, which is present in three children from two Turkish families. This variant, referred to as IKKα, 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, IKKα abolishes the kinase activity of IKKα, leading to impaired activation of the non-canonical NF-κB pathway. Patients carrying IKKα 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 IKKα variant that results in early embryonic lethality in humans, the deficiency of IKKα'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 IKKα in humans.
IKKα 是一种多功能丝氨酸/苏氨酸激酶，可控制各种依赖或不依赖其激酶活性的生物学过程。然而，由于尚未报道会破坏其激酶活性的双等位基因变异体，因此 IKKα 的激酶功能在人类生理学中的重要性仍不清楚。在这项研究中，我们在两个土耳其家庭的 3 名儿童中发现了 IKKα 激酶结构域中的纯合性胚系错义变异体。该变体称为 IKKα，位于激酶结构域的激活片段中，并影响负责协调 ATP 结合的镁原子的保守（DF/LG）基序。结果，IKKα 消除了 IKKα 的激酶活性，导致非典型 NF-κB 途径的激活受损。携带 IKKα 的患者表现出一系列免疫系统异常，包括次级淋巴器官缺失、低丙种球蛋白血症和 T 细胞和 B 细胞受体的多样性有限，并有自身反应的证据。总体而言，我们的研究结果表明，与导致人类早期胚胎致死的无义 IKKα 变异体不同，IKKα 的激酶活性缺失与人类的生存兼容。然而，它会严重破坏免疫系统的内稳态，突出了 IKKα 在人类中的必需且不可或缺的激酶功能。
