title: Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency.
abstract: The receptors for interferon-alpha/beta (IFN-alpha/beta) and IFN-gamma activate components of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, leading to the formation of at least two transcription factor complexes. STAT1 interacts with STAT2 and p48/IRF-9 to form the transcription factor IFN-stimulated gene factor 3 (ISGF3). STAT1 dimers form gamma-activated factor (GAF). ISGF3 is induced mainly by IFN-alpha/beta, and GAF by IFN-gamma, although both factors can be activated by both types of IFN. Individuals with mutations in either chain of the IFN-gamma receptor (IFN-gammaR) are susceptible to infection with mycobacteria. A heterozygous STAT1 mutation that impairs GAF but not ISGF3 activation has been found in other individuals with mycobacterial disease. No individuals with deleterious mutations in the IFN-alpha/beta signaling pathway have been described. We report here two unrelated infants homozygous with respect to mutated STAT1 alleles. Neither IFN-alpha/beta nor IFN-gamma activated STAT1-containing transcription factors. Like individuals with IFN-gammaR deficiency, both infants suffered from mycobacterial disease, but unlike individuals with IFN-gammaR deficiency, both died of viral disease. Viral multiplication was not inhibited by recombinant IFN-alpha/beta in cell lines from the two individuals. Inherited impairment of the STAT1-dependent response to human IFN-alpha/beta thus results in susceptibility to viral disease.
authors.affiliation: Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes-INSERM UMR550, Faculté de Médecine Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Dupuis
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Sami
authors.initials: S
authors.lastname: Al-Hajjar
authors.forename: Claire
authors.initials: C
authors.lastname: Fieschi
authors.forename: Ibrahim Zaid
authors.initials: IZ
authors.lastname: Al-Mohsen
authors.forename: Suliman
authors.initials: S
authors.lastname: Al-Jumaah
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Ariane
authors.initials: A
authors.lastname: Chapgier
authors.forename: Céline
authors.initials: C
authors.lastname: Eidenschenk
authors.forename: Pierre
authors.initials: P
authors.lastname: Eid
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Al Ghonaium
authors.forename: Haysam
authors.initials: H
authors.lastname: Tufenkeji
authors.forename: Husn
authors.initials: H
authors.lastname: Frayha
authors.forename: Suleiman
authors.initials: S
authors.lastname: Al-Gazlan
authors.forename: Hassan
authors.initials: H
authors.lastname: Al-Rayes
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Ion
authors.initials: I
authors.lastname: Gresser
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology; D001483:Base Sequence; D003241:Consanguinity; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D009164:Mycobacterium Infections / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D010375:Pedigree; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D017384:Sequence Deletion; D015398:Signal Transduction; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics*; D014777:Virus Diseases / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology
chemical_list: D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D007370:Interferon Type I; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma; D004247:DNA