Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6

• Published in: Journal of allergy and clinical immunology Vol. 152; no. 1; pp. 182 - 194.e7
• Main Authors: Baris, Safa, Benamar, Mehdi, Chen, Qian, Catak, Mehmet Cihangir, Martínez-Blanco, Mónica, Wang, Muyun, Fong, Jason, Massaad, Michel J., Sefer, Asena Pinar, Kara, Altan, Babayeva, Royala, Eltan, Sevgi Bilgic, Yucelten, Ayse Deniz, Bozkurtlar, Emine, Cinel, Leyla, Karakoc-Aydiner, Elif, Zheng, Yumei, Wu, Hao, Ozen, Ahmet, Schmitz-Abe, Klaus, Chatila, Talal A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2023
• Subjects: Child; Dermatitis, Atopic - genetics; Eosinophilia - genetics; Gain of Function Mutation; Humans; Hypersensitivity - genetics; Inborn errors of immunity; Jakinibs; Janus kinase inhibitors; primary atopic disorders; STAT6; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - metabolism; Th2 Cells; Transcription Factors - genetics; gain-of-function mutation; AD; Jakinibs; WES; Treg; Inborn errors of immunity; IEI; HIES; IL-4R; GFP; p; primary atopic disorders; STAT; APC; Janus kinase inhibitors; JAK; CRTH2; STAT6; SH2; cTFH; WT; GOF
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2023.01.023

[Display omitted] Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses. This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations. Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed. This study reports a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia, and elevated IgE. Naive lymphocytes from the affected patient displayed increased TH2- and suppressed TH1- and TH17-cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized TH1 and TH17 cells, suppressed the eosinophilia, and improved the patient’s atopic dermatitis. This study identified a novel inborn error of immunity due to a STAT6 gain-of-function mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder.