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 Chaussabel, Saleh Al-Muhsen, Jean Laurent Casanova, Stéphanie Boisson-Dupuis

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


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 (US)
Pages (from-to)5896-5906
Number of pages11
Issue number26
StatePublished - Dec 23 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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