A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

Joëlle Khourieh, Geetha Rao, Tanwir Habib, Danielle T. Avery, Alain Lefèvre-Utile, Marie Olivia Chandesris, Abdelaziz Belkadi, Maya Chrabieh, Hanan Alwaseem, Virginie Grandin, Françoise Sarrot-Reynauld, Agathe Sénéchal, Olivier Lortholary, Xiao Fei Kong, Stéphanie Boisson-Dupuis, Capucine Picard, Anne Puel, Vivien Béziat, Qian Zhang, Laurent AbelHenrik Molina, Nico Marr, Stuart G. Tangye, Jean Laurent Casanova, Bertrand Boisson

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Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients' primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

Original languageEnglish
Pages (from-to)16463-16472
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number33
Publication statusPublished - 13 Aug 2019



  • dominant negative
  • hyper IgE syndrome
  • immunodeficiency
  • infectious diseases
  • STAT3

ASJC Scopus subject areas

  • General

Cite this

Khourieh, J., Rao, G., Habib, T., Avery, D. T., Lefèvre-Utile, A., Chandesris, M. O., Belkadi, A., Chrabieh, M., Alwaseem, H., Grandin, V., Sarrot-Reynauld, F., Sénéchal, A., Lortholary, O., Kong, X. F., Boisson-Dupuis, S., Picard, C., Puel, A., Béziat, V., Zhang, Q., ... Boisson, B. (2019). A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance. Proceedings of the National Academy of Sciences of the United States of America, 116(33), 16463-16472. https://doi.org/10.1073/pnas.1901409116