Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.
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.
Chapgier
Ariane
A
Laboratory of Human Genetics of Infectious Diseases, University of Paris René Descartes, INSERM U550, Necker Medical School, Paris, France.
Boisson-Dupuis
Stéphanie
S
Jouanguy
Emmanuelle
E
Vogt
Guillaume
G
Feinberg
Jacqueline
J
Prochnicka-Chalufour
Ada
A
Casrouge
Armanda
A
Yang
Kun
K
Soudais
Claire
C
Fieschi
Claire
C
Santos
Orchidée Filipe
OF
Bustamante
Jacinta
J
Picard
Capucine
C
de Beaucoudrey
Ludovic
L
Emile
Jean-François
JF
Arkwright
Peter D
PD
Schreiber
Robert D
RD
Rolinck-Werninghaus
Claudia
C
Rösen-Wolff
Angela
A
Magdorf
Klaus
K
Roesler
Joachim
J
Casanova
Jean-Laurent
JL
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
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