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

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 () and Baran Erman ()
Additional contact information
Gökhan Cildir: University of South Australia and SA Pathology
Umran Aba: Hacettepe University
Damla Pehlivan: Hacettepe University
Denis Tvorogov: University of South Australia and SA Pathology
Nicholas I. Warnock: University of South Australia and SA Pathology
Canberk Ipsir: Hacettepe University
Elif Arik: Gaziantep University Faculty of Medicine
Chung Hoow Kok: University of South Australia and SA Pathology
Ceren Bozkurt: Hacettepe University
Sidem Tekeoglu: Hacettepe University
Gaye Inal: Gaziantep University Faculty of Medicine
Mahmut Cesur: Gaziantep University Faculty of Medicine
Ercan Kucukosmanoglu: Gaziantep University Faculty of Medicine
Ibrahim Karahan: Gaziantep University Faculty of Medicine
Berna Savas: Ankara University Faculty of Medicine
Deniz Balci: Bahcesehir University School of Medicine
Ayhan Yaman: Bahcesehir Liv Hospital
Nazli Deveci Demirbaş: Ankara University Faculty of Medicine
Ilhan Tezcan: Hacettepe University Faculty of Medicine, İhsan Doğramacı Children’s Hospital
Sule Haskologlu: Ankara University Faculty of Medicine
Figen Dogu: Ankara University Faculty of Medicine
Aydan Ikinciogulları: Ankara University Faculty of Medicine
Ozlem Keskin: Gaziantep University Faculty of Medicine
Damon J. Tumes: University of South Australia and SA Pathology
Baran Erman: Hacettepe University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54345-4

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