Zinc finger protein 341
DNA-binding transcription activator activity
ZNF341 controls STAT3 expression and thereby immunocompetence.
Signal transducer and activator of transcription 3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled, and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES). We investigated patients of four consanguineous families 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 STAT3 expression and diminished T helper 17 cell numbers, in absence of <i>STAT3</i> mutations. We identified two distinct homozygous nonsense mutations in <i>ZNF341</i>, which encodes a zinc finger transcription factor. Wild-type ZNF341 bound to and activated the <i>STAT3</i> promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in <i>ZNF341</i> account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.