Novel Mutations of TYK2 Leading to Divergent Clinical Phenotypes

Abstract TYK2 deficiency is a rare Primary immunodeficiency disease caused by loss of function mutations of TYK2 gene, which is initially proposed as a subset of Hyper IgE syndrome (HIES). However, accumulating evidence suggest TYK2 deficient patients do not necessarily present with HIES characteristics, indicating a vacuum of knowledge on the exact roles of TYK2 in human immune system. Here we describe five more TYK2 deficient cases presenting with or without hyper IgE levels, atopy and distinct pathogen infection profile, which are caused by novel TYK2 mutations. These mutations were all found by high throughout sequencing and confirmed by Sanger sequencing. Pathogenic effects were confirmed by qRT-PCR and western blot. Peripheral blood mononulear cells (PBMCs) from these patients showed heterogenous responses to various cytokines treatment, including IFN-a/b/g, IL-6, IL-10, IL12 and IL-23. The homeostasis of lymphocytes is also disrupted. Based on our findings, we propose that TYK2 works as a multi-tasker in orchestrating various cytokines signaling pathways, differentially combined defects of which account for the expressed clinical manifestations.