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

KL Willmann, S Klaver, F Dogu, E Santos-Valente, W Garncarz, I Bilic, E Mace, E Salzer, CD Conde, H Sic, P Majek, PP Banerjee, GI Vladimer, S Haskologlu, MG Bolkent, A Kupesiz, A Condino-Neto, J Colinge, G Superti-Furga, WF PicklMenno van Zelm, H Eibel, JS Orange, A Ikinciogullari, K 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-kappa 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-kappa 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 languageUndefined/Unknown
Number of pages13
JournalNature Communications
Publication statusPublished - 2014

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  • EMC MM-02-72-01

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