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

Vivien Béziat, Juan Li, Jian Xin Lin, Cindy S. Ma, Peng Li, Aziz Bousfiha, Isabelle Pellier, Samaneh Zoghi, Safa Baris, Sevgi Keles, Paul Gray, Ning Du, Yi Wang, Yoann Zerbib, Romain Lévy, Thibaut Leclercq, Frédégonde About, Ai Ing Lim, Geetha Rao, Kathryn PayneSimon J. Pelham, Danielle T. Avery, Elissa K. Deenick, Bethany Pillay, Janet Chou, Romain Guery, Aziz Belkadi, Antoine Guérin, Mélanie Migaud, Vimel Rattina, Fatima Ailal, Ibtihal Benhsaien, Matthieu Bouaziz, Tanwir Habib, Damien Chaussabel, Nico Marr, Jamel El-Benna, Bodo Grimbacher, Orli Wargon, Jacinta Bustamante, Bertrand Boisson, Ingrid Müller-Fleckenstein, Bernhard Fleckenstein, Marie Olivia Chandesris, Matthias Titeux, Sylvie Fraitag, Marie Alexandra Alyanakian, Marianne Leruez-Ville, Capucine Picard, Isabelle Meyts, James P. Di Santo, Alain Hovnanian, Ayper Somer, Ahmet Ozen, Nima Rezaei, Talal A. Chatila, Laurent Abel, Warren J. Leonard, Stuart G. Tangye, Anne Puel, Jean Laurent Casanova

Research output: Contribution to journalArticlepeer-review

130 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbereaat4956
JournalScience immunology
Volume3
Issue number24
DOIs
StatePublished - 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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