title: A novel form of human STAT1 deficiency impairing early but not late responses to interferons.
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.
authors.affiliation: St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Kong
authors.forename: Michael
authors.initials: M
authors.lastname: Ciancanelli
authors.forename: Sami
authors.initials: S
authors.lastname: Al-Hajjar
authors.forename: Laia
authors.initials: L
authors.lastname: Alsina
authors.forename: Timothy
authors.initials: T
authors.lastname: Zumwalt
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Magali
authors.initials: M
authors.lastname: Audry
authors.forename: Carolina
authors.initials: C
authors.lastname: Prando
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bryant
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kreins
authors.forename: Dusan
authors.initials: D
authors.lastname: Bogunovic
authors.forename: Rabih
authors.initials: R
authors.lastname: Halwani
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Zhang
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
mesh_terms: D001419:Bacteria / Q000472:pathogenicity; D001424:Bacterial Infections / Q000188:drug therapy* / Q000209:etiology; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D019281:Dimerization; D005260:Female; D006720:Homozygote; D006801:Humans; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation; D021381:Protein Transport; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma; D008156:Luciferases