LAUSR

Complete TYK2 deficiency (IMMUNODEFICIENCY 35 OMIM (611521)) is a rare disorder, inherited as an autosomal recessive (AR) trait, which has been previously described in nine patients from seven unrelated kindreds [1–3]. It was first reported in a Japanese patient with mycobacterial and viral disease associated with hyper IgE syndrome [1]. Later, investigation of five more families with complete AR TYK2 deficiency showed that the main clinical phenotype of the patients was mycobacterial and/or viral disease without hyper IgE syndrome [2]. In addition, another patient with some features of hyper IgE (eczema, skin abscesses, respiratory infections and IgE levels > 1000 IU/ml) and TYK2 deficiencywas described [3]. TYK2 is a member of the Janus kinase family (JAK1, 2, 3, and TYK2) that plays a significant role in signaling receptors of group 1 and 2 of cytokines, namely IL-10, IL-12, IL-23, and IFN-α/β. Briefly, attachment of the ligand to the cytokine receptor induces conformational changes and activation of the JAKs kinases via phosphorylation. The JAKs then phosphorylate the intracellular part of the receptor which create a docking site for the signal transducer and activator of transcriptions (STATs) molecules. STATs are subsequently phosphorylated and translocated to the nucleus to activate the transcription of target genes [4]. TYK2 protein is essential for mediating cytokine signaling and its defect will interfere with IFN-α, IFN-β, IL-12, IL-23, and IL10 pathways [4]. Attachment of IL-12 to IL-12 receptor (IL12Rβ1 and IL-12Rβ2) and IL-23 to IL-23R (IL-12Rβ1 and IL-23R) induce the transcription of IFN-γ in the nucleus, which is crucial for anti-mycobacterial immunity [5]. IFN-α/β signals are also essential for transcription of various immune factors that help to defend against viruses [6]. As a result, patients with complete AR TYK2 deficiency suffered from intracellular bacterial infections such as Mycobacterium, Salmonella, Brucella, and various viral infections like herpes simplex virus (HSV) group [2, 6]. This is referred to as syndromic, opposed to isolated, Mendelian susceptibility to mycobacterial disease (MSMD) [7]. TYK2 has four main domains including 4.1, ezrin, radixin, moesin (FERM), SH2-like, pseudokinase, and kinase. Patients with complete ARTYK2 deficiency display deleterious loss-offunction (LOF) mutations in the FERM (S50Hfs*1, C70Hfs*21, E154*, and P216Hfs*14), pseudokinase (R638* and L767*), and kinase domains (T1106Hfs*4). They are all LOF and lead to the non-expression of TYK2 [1–3]. On the other hand, isolated mycobacterial infection, including MSMD or tuberculosis in particular, can be caused by homozygosity for the TYK2 P1104A common variant [8]. In this study, we investigated a patient withmycobacterial and viral infections having a mutation in TYK2 exon 7 encoding the FERM domain of the TYK2 protein.