STAT3 haploinsufficiency is associated with autosomal dominant hyper-IgE syndrome.

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 () 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 nonsense mutation that led to rapid decay of the mutant mRNA and protein, leading to haploinsufficiency. To explore STAT3 heterozygosity, we created a haploinsufficient () mouse model in which we found that mice had increased IgE serum levels, reduced T17 cell differentiation, and were susceptible to a cutaneous infection. Together, our findings provide mechanistic evidence for the impact of haploinsufficiency in 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.