Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.

Ariane Chapgier (1) , Stéphanie Boisson-Dupuis (1) , Emmanuelle Jouanguy (1, 2) , Guillaume Vogt (1) , Jacqueline Feinberg (1) , Ada Prochnicka-Chalufour (3) , Armanda Casrouge (1) , Kun Yang (1, 2) , Claire Soudais (1) , Claire Fieschi (1, 4) , Orchidée Filipe Santos (1) , Jacinta Bustamante (1) , Capucine Picard (1, 5) , Ludovic de Beaucoudrey (1) , Jean-François Emile (6) , Peter D Arkwright (7) , Robert D Schreiber (8) , Claudia Rolinck-Werninghaus (9) , Angela Rösen-Wolff (10) , Klaus Magdorf (9) , Joachim Roesler (10) , Jean-Laurent Casanova (1, 2, 11)

1 Inserm U980 - Génétique Humaine des Maladies Infectieuses
2 FRENCH CHINESE LABORATORY OF GENETICS - French Chinese laboratory of Genetics
3 Résonance Magnétique Nucléaire des Biomolécules
4 Service d'immunologie clinique
5 CEREDIH - Centre de Référence Déficits Immunitaires Héréditaires
6 Service d'anatomie pathologique [CHU Ambroise-Paré]
7 University of Manchester [Manchester]
8 Department of Pathology and Immunology [Washington University in St. Louis]
9 DEPARTMENT OF PEDIATRIC PNEUMOLOGY AND IMMUNOLOGY - Department of Pediatric Pneumology and Immunology
10 DEPARTMENT OF PEDIATRICS - Department of Pediatrics
11 Service d'immuno-hématologie pédiatrique [CHU Necker]

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.

Domaines: Immunité adaptative

Ariane Chapgier, Stéphanie Boisson-Dupuis, Emmanuelle Jouanguy, Guillaume Vogt, Jacqueline Feinberg, et al.. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease.. PLoS Genetics, 2006, 2 (8), pp.e131. ⟨10.1371/journal.pgen.0020131⟩. ⟨hal-00164335⟩