A novel form of human STAT1 deficiency impairing early but not late responses to interferons

Xiao Fei Kong, Michael Ciancanelli, Sami Al-Hajjar, Laia Alsina, Timothy Zumwalt, Jacinta Bustamante, Jacqueline Feinberg, Magali Audry, Carolina Prando, Vanessa Bryant, Alexandra Kreins, Dusan Bogunovic, Rabih Halwani, Xin Xin Zhang, Laurent Abel, Damien J. Chaussabel, Saleh Al-Muhsen, Jean Laurent Casanova, Stéphanie Boisson-Dupuis

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Autosomal recessive STAT1 deficiency is associated with impaired cellular responses to interferons and susceptibility to intracellular bacterial and viral infections. We report here a new form of partial STAT1 deficiency in 2 siblings presenting mycobacterial and viral diseases. Both carried a homozygous missense mutation replacing a lysine with an asparagine residue at position 201 (K201N) of STAT1. This mutation causes the abnormal splicing out of exon 8 from most STAT1 mRNAs, thereby decreasing (by ∼ 70%) STAT1 protein levels. The mutant STAT1 proteins are not intrinsically deleterious, in terms of tyrosine phosphorylation, dephosphorylation, homodimerization into γ-activating factor and heterotrimerization into ISGF-3, binding to specific DNA elements, and activation of the transcription. Interestingly, the activation of γ-activating factor and ISGF3 was impaired only at early time points in the various cells from patient (within 1 hour of stimulation), whereas sustained impairment occurs in other known forms of complete and partial recessive STAT1 deficiency. Consequently, delayed responses were normal; however, the early induction of interferon-stimulated genes was selectively and severely impaired. Thus, the early cellular responses to human interferons are critically dependent on the amount of STAT1 and are essential for the appropriate control of mycobacterial and viral infections.

Original languageEnglish
Pages (from-to)5896-5906
Number of pages11
JournalBlood
Volume116
Issue number26
DOIs
Publication statusPublished - 23 Dec 2010
Externally publishedYes

Fingerprint

Virus Diseases
STAT1 Transcription Factor
Interferons
Interferon-Stimulated Gene Factor 3
Chemical activation
Phosphorylation
Asparagine
Missense Mutation
Mutant Proteins
Transcription
Bacterial Infections
Transcriptional Activation
Lysine
Tyrosine
Siblings
Exons
Genes
Messenger RNA
Mutation
DNA

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Kong, X. F., Ciancanelli, M., Al-Hajjar, S., Alsina, L., Zumwalt, T., Bustamante, J., ... Boisson-Dupuis, S. (2010). A novel form of human STAT1 deficiency impairing early but not late responses to interferons. Blood, 116(26), 5896-5906. https://doi.org/10.1182/blood-2010-04-280586.

A novel form of human STAT1 deficiency impairing early but not late responses to interferons. / Kong, Xiao Fei; Ciancanelli, Michael; Al-Hajjar, Sami; Alsina, Laia; Zumwalt, Timothy; Bustamante, Jacinta; Feinberg, Jacqueline; Audry, Magali; Prando, Carolina; Bryant, Vanessa; Kreins, Alexandra; Bogunovic, Dusan; Halwani, Rabih; Zhang, Xin Xin; Abel, Laurent; Chaussabel, Damien J.; Al-Muhsen, Saleh; Casanova, Jean Laurent; Boisson-Dupuis, Stéphanie.

In: Blood, Vol. 116, No. 26, 23.12.2010, p. 5896-5906.

Research output: Contribution to journalArticle

Kong, XF, Ciancanelli, M, Al-Hajjar, S, Alsina, L, Zumwalt, T, Bustamante, J, Feinberg, J, Audry, M, Prando, C, Bryant, V, Kreins, A, Bogunovic, D, Halwani, R, Zhang, XX, Abel, L, Chaussabel, DJ, Al-Muhsen, S, Casanova, JL & Boisson-Dupuis, S 2010, 'A novel form of human STAT1 deficiency impairing early but not late responses to interferons', Blood, vol. 116, no. 26, pp. 5896-5906. https://doi.org/10.1182/blood-2010-04-280586.
Kong XF, Ciancanelli M, Al-Hajjar S, Alsina L, Zumwalt T, Bustamante J et al. A novel form of human STAT1 deficiency impairing early but not late responses to interferons. Blood. 2010 Dec 23;116(26):5896-5906. https://doi.org/10.1182/blood-2010-04-280586.
Kong, Xiao Fei ; Ciancanelli, Michael ; Al-Hajjar, Sami ; Alsina, Laia ; Zumwalt, Timothy ; Bustamante, Jacinta ; Feinberg, Jacqueline ; Audry, Magali ; Prando, Carolina ; Bryant, Vanessa ; Kreins, Alexandra ; Bogunovic, Dusan ; Halwani, Rabih ; Zhang, Xin Xin ; Abel, Laurent ; Chaussabel, Damien J. ; Al-Muhsen, Saleh ; Casanova, Jean Laurent ; Boisson-Dupuis, Stéphanie. / A novel form of human STAT1 deficiency impairing early but not late responses to interferons. In: Blood. 2010 ; Vol. 116, No. 26. pp. 5896-5906.
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