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

Katharina L. Willmann, Stefanie Klaver, Figen Do U, Elisangela Santos-Valente, Wojciech Garncarz, Ivan Bilic, Emily Mace, Elisabeth Salzer, Cecilia Domínguez Conde, Heiko Sic, Peter Májek, Pinaki P. Banerjee, Gregory I. Vladimer, Azule Haskologlu, Musa Gökalp Bolkent, Alphan Küpesiz, Antonio Condino-Neto, Jacques Colinge, Giulio Superti-Furga, Winfried F. PicklMenno C. Van Zelm, Hermann Eibel, Jordan S. Orange, Aydan Ikinciogullari, Kaan Boztug

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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- B-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- B 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.

Original languageEnglish
Article number5360
Number of pages13
JournalNature Communications
Publication statusPublished - 2014
Externally publishedYes

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