title: Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.
abstract: The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)-induced gamma-activating factor-mediated immunity and interferon alpha (IFNA)-induced interferon-stimulated genes factor 3-mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor-mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3-mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes, INSERM U550, Necker Medical School, Paris, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Chapgier
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vogt
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Ada
authors.initials: A
authors.lastname: Prochnicka-Chalufour
authors.forename: Armanda
authors.initials: A
authors.lastname: Casrouge
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Claire
authors.initials: C
authors.lastname: Soudais
authors.forename: Claire
authors.initials: C
authors.lastname: Fieschi
authors.forename: Orchidée Filipe
authors.initials: OF
authors.lastname: Santos
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Ludovic
authors.initials: L
authors.lastname: de Beaucoudrey
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Claudia
authors.initials: C
authors.lastname: Rolinck-Werninghaus
authors.forename: Angela
authors.initials: A
authors.lastname: Rösen-Wolff
authors.forename: Klaus
authors.initials: K
authors.lastname: Magdorf
authors.forename: Joachim
authors.initials: J
authors.lastname: Roesler
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007110:Immunity, Active / Q000235:genetics; D007223:Infant; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation; D009164:Mycobacterium Infections / Q000209:etiology / Q000235:genetics*; D010375:Pedigree; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection / Q000379:methods
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C096192:GAS1 protein, human; D058851:GPI-Linked Proteins; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D008565:Membrane Proteins; D050505:Mutant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma