A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

Abstract

Heterozygosity for human <i>signal transducer and activator of transcription 3</i> (<i>STAT3</i>) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, <i>ZNF341</i> ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the <i>STAT3</i> promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with <i>STAT3</i> DN mutations, ZNF341-deficient patients lack T helper 17 (T_H17) cells, have an excess of T_H2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the <i>STAT3</i> transcription-dependent autoinduction and sustained activity of STAT3.