Published January 1, 2023 | Version v1
Journal article Open

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

Creators

  • 1. Gene Engn & Biotechnol Inst, TUBITAK Marmara Res Ctr, Gebze, Turkiye
  • 2. Marmara Univ, Sch Med, Dept Dermatol, Istanbul, Turkiye
  • 3. Marmara Univ, Sch Med, Dept Pathol, Istanbul, Turkiye

Description

Background: Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses. Objectives: This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations.Methods: Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed.Results: 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.Conclusions: 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. (J Allergy Clin Immunol 2023;152:182-94.)

Files

bib-b6f68dbd-644c-4f5a-8d0b-23a3cbac64f1.txt

Files (424 Bytes)

Name Size Download all
md5:9ba35544f0bb949a955168531e37d11a
424 Bytes Preview Download