ZNF341 controls STAT3 expression and thereby immunocompetence

Signal transducer and activator of transcription 3 ( STAT3) is a central regulator of immune homeostasis. STAT3levels are strictly controlled, and STAT3impairment contributes to several diseases including the monogenic autosomal-dominant hyper– immunoglobulin E(IgE) syndrome (AD-HIES). We investigated patients of four consanguineousfamilies with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3expression and diminished T helper 17 cellnumbers, in absence of STAT3mutations. We identified two distinct homozygous nonsense mutationsin ZNF341 , which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutationsin ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.