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Novel mutations of TYK2 leading to divergent clinical phenotypes
  • +9
  • Ge Lv,
  • Gan Sun,
  • Peilin Wu,
  • Xiao Du,
  • Ting Zeng,
  • Wen Wen,
  • Lina Zhou,
  • Yun-Fei An,
  • Xue-Mei Tang,
  • Tingyan He,
  • Xiao-dong Zhao,
  • Hongqiang Du
Ge Lv
Chongqing Medical University Affiliated Children's Hospital
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Gan Sun
Chongqing Medical University Affiliated Children's Hospital
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Peilin Wu
Fujian Medical University Affiliated Fuzhou First Hospital
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Xiao Du
Chongqing Medical University Affiliated Children's Hospital
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Ting Zeng
Chongqing Medical University Affiliated Children's Hospital
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Wen Wen
Chongqing Medical University Affiliated Children's Hospital
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Lina Zhou
Chongqing Medical University Affiliated Children's Hospital
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Yun-Fei An
Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders
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Xue-Mei Tang
Children’s Hospital, Chongqing Medical University
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Tingyan He
Shenzhen Children's Hospital
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Xiao-dong Zhao
Chongqing Medical University Affiliated Children's Hospital
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Hongqiang Du
Chongqing Medical University Affiliated Children's Hospital
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Abstract

Background: 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. Method: Pathogenic effects of patients were confirmed by qRT-PCR, western blot and protein stability assays. The responses to cytokines including IFN-α/β/γ, IL-6, IL-10, IL12 and IL-23 of peripheral blood mononuclear cells (PBMCs) from these patients were detected by western blot, qRT-PCR and flow cytometry. The differentiation of T and B cells were detected by flow cytometry. Results: 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. The patients showed heterogenous responses to various cytokine treatments, including IFN-α/β/γ, IL-6, IL-10, IL12 and IL-23. The homeostasis of lymphocytes is also disrupted. Conclusion: 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.

Peer review status:IN REVISION

18 May 2021Submitted to Pediatric Allergy and Immunology
28 May 2021Reviewer(s) Assigned
10 Jun 2021Review(s) Completed, Editorial Evaluation Pending
15 Jun 2021Editorial Decision: Revise Major