Human ZNF341 deficiency underlies a recessive form of hyper IgE syndrome by disrupting STAT3 transcription-dependent STAT3 activity. Human ZNF341 deficiency underlies a recessive form of hyper IgE syndrome by disrupting STAT3 transcription-dependent STAT3 activity

Heterozygosity for human STAT3 dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-IgE syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341. ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including, most notably the STAT3 promoter. The patients’ cells have low basal levels of STAT3 mRNA and protein. The auto-induction of STAT3 production, activation, and function by STAT3-activating cytokines is particularly strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack Th17 cells, have an excess of Th2 cells, and 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 STAT3 transcription-dependent auto-induction and sustained activity of STAT3. Overall design: Total of 11 samples were analyzed from two micorarray platforms (Clariom S Human and HuGene2_0). Clariom S human array was used for 5 samples and HuGene was used for 6 T cell samples. Out of 5 samples from Clariom array, 3 were control samples with Beads with IL-6 stimulation, and 2 patients (P4 and P7) with Beads with IL-6 stimulation. Out of 6 samples from HuGene array, 4 were control samples and two patients (P4 and P7).