Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity

Katharina L. Willmann, Stefanie Klaver, Figen Doğu, Elisangela Santos-Valente, Wojciech Garncarz, Ivan Bilic, Emily Mace, Elisabeth Salzer, Cecilia Domínguez Conde, Heiko Sic, Peter Májek, Pinaki P. Banerjee, Gregory I. Vladimer, Şule Haskoloğlu, Musa Gökalp Bolkent, Alphan Küpesiz, Antonio Condino-Neto, Jacques Colinge, Giulio Superti-Furga, Winfried F. Pickl, Menno C. van Zelm, Hermann Eibel, Jordan S. Orange, Aydan Ikincioğulları and Kaan Boztuğ ()
Additional contact information
Katharina L. Willmann: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Stefanie Klaver: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Figen Doğu: Ankara University Medical School
Elisangela Santos-Valente: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Wojciech Garncarz: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Ivan Bilic: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Emily Mace: Center for Human Immunobiology, Baylor College of Medicine and Texas Children’s Hospital
Elisabeth Salzer: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Cecilia Domínguez Conde: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Heiko Sic: Centre of Chronic Immunodeficiency, University Medical Centre Freiburg
Peter Májek: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Pinaki P. Banerjee: Center for Human Immunobiology, Baylor College of Medicine and Texas Children’s Hospital
Gregory I. Vladimer: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Şule Haskoloğlu: Ankara University Medical School
Musa Gökalp Bolkent: Ankara University Medical School
Alphan Küpesiz: Akdeniz University Medical School
Antonio Condino-Neto: Institute of Biomedical Sciences, University of São Paulo
Jacques Colinge: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Giulio Superti-Furga: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria
Winfried F. Pickl: Christian Doppler Laboratory for Immunomodulation and Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna
Menno C. van Zelm: Erasmus MC, University Medical Center
Hermann Eibel: Centre of Chronic Immunodeficiency, University Medical Centre Freiburg
Jordan S. Orange: Center for Human Immunobiology, Baylor College of Medicine and Texas Children’s Hospital
Aydan Ikincioğulları: Ankara University Medical School
Kaan Boztuğ: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. Here we study patients suffering from recurrent bacterial, viral and Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF-κB-inducing kinase). Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF-κB signalling. Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression. Although overall T-cell numbers are normal, both follicular helper and memory T cells are perturbed. Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses. Collectively, our data illustrate the non-redundant role for NIK in human immune responses, demonstrating that loss-of-function mutations in NIK can cause multiple aberrations of lymphoid immunity.

Date: 2014
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DOI: 10.1038/ncomms6360

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