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 Abel & 5 others Henrik Molina, Nico Marr, Stuart G. Tangye, Jean Laurent Casanova, Bertrand Boisson

Research output: Contribution to journalArticle

Abstract

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
Volume116
Issue number33
DOIs
Publication statusPublished - 13 Aug 2019

Fingerprint

Job Syndrome
Mutant Proteins
Mutation
B-Lymphocytes
Alleles
STAT3 Transcription Factor
Introns
Tyrosine
Exons
Mass Spectrometry
Proteins
Leukocytes
Complementary DNA
Phosphorylation
Cytokines
T-Lymphocytes
DNA

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance. / Khourieh, Joëlle; Rao, Geetha; Habib, Tanwir; Avery, Danielle T.; Lefèvre-Utile, Alain; Chandesris, Marie Olivia; Belkadi, Abdelaziz; Chrabieh, Maya; Alwaseem, Hanan; Grandin, Virginie; Sarrot-Reynauld, Françoise; Sénéchal, Agathe; Lortholary, Olivier; Kong, Xiao Fei; Boisson-Dupuis, Stéphanie; Picard, Capucine; Puel, Anne; Béziat, Vivien; Zhang, Qian; Abel, Laurent; Molina, Henrik; Marr, Nico; Tangye, Stuart G.; Casanova, Jean Laurent; Boisson, Bertrand.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 33, 13.08.2019, p. 16463-16472.

Research output: Contribution to journalArticle

Khourieh, J, Rao, G, Habib, T, Avery, DT, Lefèvre-Utile, A, Chandesris, MO, Belkadi, A, Chrabieh, M, Alwaseem, H, Grandin, V, Sarrot-Reynauld, F, Sénéchal, A, Lortholary, O, Kong, XF, Boisson-Dupuis, S, Picard, C, Puel, A, Béziat, V, Zhang, Q, Abel, L, Molina, H, Marr, N, Tangye, SG, Casanova, JL & 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, vol. 116, no. 33, pp. 16463-16472. https://doi.org/10.1073/pnas.1901409116
Khourieh, Joëlle ; Rao, Geetha ; Habib, Tanwir ; Avery, Danielle T. ; Lefèvre-Utile, Alain ; Chandesris, Marie Olivia ; Belkadi, Abdelaziz ; Chrabieh, Maya ; Alwaseem, Hanan ; Grandin, Virginie ; Sarrot-Reynauld, Françoise ; Sénéchal, Agathe ; Lortholary, Olivier ; Kong, Xiao Fei ; Boisson-Dupuis, Stéphanie ; Picard, Capucine ; Puel, Anne ; Béziat, Vivien ; Zhang, Qian ; Abel, Laurent ; Molina, Henrik ; Marr, Nico ; Tangye, Stuart G. ; Casanova, Jean Laurent ; Boisson, Bertrand. / A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 33. pp. 16463-16472.
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AU - Khourieh, Joëlle

AU - Rao, Geetha

AU - Habib, Tanwir

AU - Avery, Danielle T.

AU - Lefèvre-Utile, Alain

AU - Chandesris, Marie Olivia

AU - Belkadi, Abdelaziz

AU - Chrabieh, Maya

AU - Alwaseem, Hanan

AU - Grandin, Virginie

AU - Sarrot-Reynauld, Françoise

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AU - Lortholary, Olivier

AU - Kong, Xiao Fei

AU - Boisson-Dupuis, Stéphanie

AU - Picard, Capucine

AU - Puel, Anne

AU - Béziat, Vivien

AU - Zhang, Qian

AU - Abel, Laurent

AU - Molina, Henrik

AU - Marr, Nico

AU - Tangye, Stuart G.

AU - Casanova, Jean Laurent

AU - Boisson, Bertrand

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N2 - 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.

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