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

Autor: Gökhan Cildir, Umran Aba, Damla Pehlivan, Denis Tvorogov, Nicholas I. Warnock, Canberk Ipsir, Elif Arik, Chung Hoow Kok, Ceren Bozkurt, Sidem Tekeoglu, Gaye Inal, Mahmut Cesur, Ercan Kucukosmanoglu, Ibrahim Karahan, Berna Savas, Deniz Balci, Ayhan Yaman, Nazli Deveci Demirbaş, Ilhan Tezcan, Sule Haskologlu, Figen Dogu, Aydan Ikinciogulları, Ozlem Keskin, Damon J. Tumes, Baran Erman
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Nature Communications, Vol 15, Iss 1, Pp 1-18 (2024)
Druh dokumentu: article
ISSN: 2041-1723
DOI: 10.1038/s41467-024-54345-4
Popis: Abstract 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 IKKαG167R, 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, IKKαG167R abolishes the kinase activity of IKKα, leading to impaired activation of the non-canonical NF-κB pathway. Patients carrying IKKαG167R 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.
Databáze: Directory of Open Access Journals
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