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

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Science Immunology  15 Jun 2018:
Vol. 3, Issue 24, eaat4956
DOI: 10.1126/sciimmunol.aat4956

Fingers on the trigger

Hyper–immunoglobulin E syndromes (HIESs) are rare genetic immunodeficiency diseases characterized by bacterial infections, chronic mucocutaneous candidiasis, allergies, and skeletal abnormalities that are associated with excessive TH2 responses and impaired TH17 immunity. Béziat et al. and Frey-Jakobs et al. have studied patients with an autosomal recessive form of HIES and identified mutations in the zinc finger transcription factor ZNF341 as the culprit. Loss-of-function mutations encoding truncated forms of ZNF341 interfered with its ability to recognize a bipartite binding site located in the promoter of STAT3, the transcription factor mutated in most cases of autosomal dominant HIES. ZNF341-supported transcription of STAT3 is a key upstream regulatory step needed to trigger the normal induction of the TH17 differentiation pathway. These findings reveal a previously unappreciated layer of transcriptional regulation controlling JAK-STAT signaling.


Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) 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, ZNF341. ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 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 STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 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 STAT3 transcription–dependent autoinduction and sustained activity of STAT3.

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