Stat3 Haploinsufficiency Is Associated With Autosomal Dominant Hyper-Ige Syndrome Publisher



V Andreani VIRGINIA ; Aj Forde Aaron JAMES ; M Fliegauf MANFRED ; NULL ; NULL ; N Ott NILS ; S Saghafi SHIVA ; L Vornholz LARSEN ; Se Isay Sophie E ; J Ruland JURGEN
Source: Science Advances Published:2025

Abstract

The autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency, which originates from heterozygous missense mutations in the signal transducer and activator of transcription 3 (STAT3) gene. It is accepted that most STAT3 variants causing AD-HIES are dominant negative. Whether haploinsufficient mutations cause a phenotype in humans is still debated. We report on a family with a heterozygous STAT3 nonsense mutation that led to rapid decay of the mutant mRNA and protein, leading to haploinsufficiency. To explore STAT3 heterozygosity, we created a Stat3 haploinsufficient (Stat3+/−) mouse model in which we found that Stat3+/− mice had increased IgE serum levels, reduced TH17 cell differentiation, and were susceptible to a cutaneous Staphylococcus aureus infection. Together, our findings provide mechanistic evidence for the impact of haploinsufficiency in STAT3 with residual protein expression as an important cause for immune deficiency. The implications extend to the diagnosis of immunodeficiency disorders and to the design of gene therapy in situations where gene dosage matters. © 2025 Elsevier B.V., All rights reserved.