1. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease
- Author
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Claire Soudais, Capucine Picard, Angela Rösen-Wolff, Guillaume Vogt, C. Rolinck-Werninghaus, Emmanuelle Jouanguy, Jacqueline Feinberg, Jean-Laurent Casanova, Klaus Magdorf, Jacinta Bustamante, Kun Yang, Ada Prochnicka-Chalufour, Claire Fieschi, Orchidée Filipe Santos, Peter D. Arkwright, Joachim Roesler, Jean-François Emile, Robert D. Schreiber, Ludovic de Beaucoudrey, Stéphanie Boisson-Dupuis, Ariane Chapgier, Armanda Casrouge, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), French Chinese laboratory of Genetics (FRENCH CHINESE LABORATORY OF GENETICS), Rujin ospital, Shanghai II University, Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], University of Manchester [Manchester], Department of Pathology and Immunology (DEPARTMENT OF PATHOLOGY AND IMMUNOLOGY), Washington University in Saint Louis (WUSTL), Department of Pediatric Pneumology and Immunology (DEPARTMENT OF PEDIATRIC PNEUMOLOGY AND IMMUNOLOGY), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Pediatrics (DEPARTMENT OF PEDIATRICS), University Clinic Carl Gustav Carus, Dresden, Service d'immuno-hématologie pédiatrique [CHU Necker], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Service d'anatomie pathologique, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), French Chinese laboratory of Genetics ( FRENCH CHINESE LABORATORY OF GENETICS ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Department of Pathology and Immunology ( DEPARTMENT OF PATHOLOGY AND IMMUNOLOGY ), Washington University Saint Louis Missouri, Department of Pediatric Pneumology and Immunology ( DEPARTMENT OF PEDIATRIC PNEUMOLOGY AND IMMUNOLOGY ), Charité, Humboldt University of Berlin, Department of Pediatrics ( DEPARTMENT OF PEDIATRICS ), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,MESH : Mutant Proteins ,Transcription, Genetic ,DNA Mutational Analysis ,Cell Cycle Proteins ,0302 clinical medicine ,MESH : Cell Cycle Proteins ,MESH : Child ,MESH: Child ,MESH : Interferon-Stimulated Gene Factor 3, gamma Subunit ,STAT1 ,MESH: DNA Mutational Analysis ,Child ,Cells, Cultured ,0303 health sciences ,MESH : Gene Expression Regulation ,MESH : Infant ,MESH : Interferon Type II ,MESH : Protein Binding ,MESH : Genes, Dominant ,MESH: Infant ,3. Good health ,Pedigree ,STAT1 Transcription Factor ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,030220 oncology & carcinogenesis ,Child, Preschool ,MESH : DNA-Binding Proteins ,MESH: Membrane Proteins ,MESH: Models, Molecular ,MESH: Cells, Cultured ,MESH : Heterozygote ,MESH: Pedigree ,Immunology ,Alpha interferon ,MESH : DNA Mutational Analysis ,GPI-Linked Proteins ,Transfection ,03 medical and health sciences ,Interferon-gamma ,MESH: Cell Cycle Proteins ,MESH : Adolescent ,Genetics ,MESH: Protein Binding ,Humans ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,MESH: Genes, Recessive ,Alleles ,MESH: Adolescent ,Mycobacterium Infections ,MESH: Humans ,MESH: STAT1 Tra ,MESH : Immunity, Active ,MESH : Humans ,MESH: Child, Preschool ,MESH : Genes, Recessive ,Infant ,MESH: Adult ,Interferon-Stimulated Gene Factor 3, gamma Subunit ,MESH : Membrane Proteins ,MESH : Mycobacterium Infections ,Mutation ,MESH : Alleles ,MESH: Genes, Dominant ,MESH: Female ,MESH: Immunity, Active ,Models, Molecular ,Cancer Research ,MESH : Models, Biological ,MESH : Child, Preschool ,[ SDV.IMM.IA ] Life Sciences [q-bio]/Immunology/Adaptive immunology ,Loss of heterozygosity ,MESH: Mutant Proteins ,Homo (Human) ,Interferon gamma ,MESH : Female ,Genetics (clinical) ,MESH: Heterozygote ,Genes, Dominant ,MESH : Adult ,MESH: Gene Expression Regulation ,DNA-Binding Proteins ,Immunity, Active ,Infectious Diseases ,MESH : Interferon-alpha ,MESH: Interferon-Stimulated Gene Factor 3, gamma Subunit ,Female ,MESH : Mutation ,MESH: Interferon-alpha ,medicine.drug ,Protein Binding ,Research Article ,MESH : STAT1 Tra ,Adult ,Heterozygote ,MESH: Mutation ,lcsh:QH426-470 ,Adolescent ,MESH : Models, Molecular ,MESH: Interferon Type II ,MESH : Male ,Genetics/Genetics of Disease ,Genes, Recessive ,Biology ,Models, Biological ,Immunity ,MESH : Cells, Cultured ,medicine ,Allele ,MESH: Mycobacterium Infections ,Gene ,030304 developmental biology ,MESH: Alleles ,MESH: Models, Biological ,Interferon-alpha ,Membrane Proteins ,Heterozygote advantage ,MESH: Male ,lcsh:Genetics ,Gene Expression Regulation ,MESH : Pedigree ,biology.protein ,Mutant Proteins ,MESH: DNA-Binding Proteins - 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., Synopsis Mendelian susceptibility to mycobacterial disease is a rare syndrome. It is defined by the occurrence of severe disease caused by low virulence mycobacteria in otherwise healthy individuals, in whom antiviral immune response is not affected. Eleven known genetic defects, affecting five genes, have been involved in this type of deficient response to infection, involving immune-mediator molecules IL12 and interferon gamma: IL12B, IL12RB1, IFNGR1, IFNGR2, and STAT1. The signal transducer and activator of transcription-1 (STAT1) amino acid change L706S was previously shown to cause disease by impairing STAT1 phosphorylation. Here, we report two new STAT1 mutations that impair STAT1 DNA-binding activity. We show, by functional analysis of the three STAT1 mutant alleles, that they are intrinsically deleterious for both interferon gamma–induced antimycobacterial immunity, which is mediated through gamma-activated factor and for interferon alpha–induced antiviral immunity, which is mediated through interferon-stimulated genes factor 3. Interestingly, the three alleles are dominant for interferon gamma–induced gamma-activated factor–mediated antimycobacterial immunity, but recessive for interferon alpha–induced interferon-stimulated genes factor 3–mediated antiviral immunity at the cellular and clinical levels. These two new STAT1 alleles, which affect the binding of STAT1 to DNA, define distinct novel genetic causes of Mendelian susceptibility to mycobacterial disease and provide further insight into the molecular mechanism of disease.
- Published
- 2006
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