Mechanism of pathogenesis by a gain-of-function variant of STAT6 causing severe allergic diseases and potential for development of molecularly targeted drugs

Allergic diseases have been considered multifactorial diseases. However, comprehensive genome sequencing, such as whole exome analysis, is revealing a group of diseases in which single genes are deeply involved in their pathogenesis. We identified a de novo missense variant of STAT6 [NM_003153:c.1255G>A,p.(Asp419Asn)] in a severely allergic patient with atopic dermatitis, hyper IgE, eosinophilic gastroenteritis, and food allergy by whole exome sequencing analysis. STAT6 is known as a transcription factor induced by IL-4 stimulation. Stimulation with IL-4 induces STAT6 phosphorylation via the JAK-STAT pathway and dimer formation. The STAT6 dimer quickly translocates into the nucleus and ultimately activates the expression of genes specific for TH2-type immune responses. Our experiments in vitro showed that nuclear translocation of mutant STAT6 (p.Asp419Asn) is enhanced compared to wild-type STAT6. In addition, even in the absence of IL-4 stimulation, we observed the translocation of mutant STAT6 in its unphosphorylated state, which activated gene expression. Mutant STAT6 knock-in mice elicited an abnormal TH2-dominant immune response in vivo, with findings similar to those observed in patients. Our findings suggest that mutant STAT6 is a gain-of-function variant. Currently, anti-IL-4Rα monoclonal antibodies, JAK inhibitors that block the JAK-STAT pathway, and non-specific anti-inflammatory drugs such as steroids are shown to be effective in treating this disease. The pathogenesis of immune dysregulation caused by gain-of-function variants of the STAT6 gene is being elucidated. Further efforts are required to elucidate the detailed mechanisms of this disease and it will hopefully lead to the development of more essential agents that specifically regulate STAT6 activity.