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4 results on '"MESH : Mutant Proteins"'

1. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. : Activating STAT3 mutations in hepatocellular adenoma

Author

Jeanne Tran Van Nhieu, Michel Bihl, Karine Poussin, Mohamed Amessou, Paulette Bioulac-Sage, Jessica Zucman-Rossi, Charles Balabaud, Camilla Pilati, Jean-Charles Nault, Tina Izard, Valérie Paradis, Gabrielle Couchy, Genomique Fonctionnelle des Tumeurs Solides, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Labex Immuno-oncology, Centre de Recherche des Cordeliers ( CRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -École pratique des hautes études ( EPHE ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -PRES Sorbonne Paris Cité-Faculté de Médecine, Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service de Pathologie [Clichy], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Department of Cancer Biology, The Scripps Research Institute, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'Hépato-Gastro Entérologie et Oncologie Digestive, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), and This work was supported by the association pour la recherche Contre le Cancer (ARC, grant n°3194), Inserm (Réseaux de recherche clinique et réseaux de recherche en santé des populations), Collection Nationale des Carcinomes Hépatocellulaires, the Ligue Nationale Contre le Cancer ('Cartes d'identité des tumeurs' program) and the BioIntelligence collaborative program. C.P., M.A. and J-C.N. are supported by a fellowship from the MENRT, Inca and ARC, respectively. T.I. is supported by the National Institutes of Health grants GM071596, AI055894, and AI067949.

Subjects
MESH : Tyrosine, Male, Models, Molecular, MESH : Liver Neoplasms, MESH : Mutant Proteins, MESH : Aged, MESH : RNA, Small Interfering, SH2 domain, medicine.disease_cause, HNF1A, STAT3, MESH : Phosphorylation, 0302 clinical medicine, MESH : STAT3 Transcription Factor, Cytokine Receptor gp130, Immunology and Allergy, CTNNB1, MESH : Female, SOCS3, Phosphorylation, RNA, Small Interfering, 0303 health sciences, Mutation, Liver Neoplasms, DNA, Neoplasm, MESH : Adult, Middle Aged, SAA, 3. Good health, MESH : Cytokine Receptor gp130, JAK1, src-Family Kinases, JAK2, MESH : Dimerization, 030220 oncology & carcinogenesis, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Female, MESH : DNA, Neoplasm, MESH : Mutation, CRP, IL6ST, Dimerization, Tyrosine kinase, Src, Signal Transduction, Proto-oncogene tyrosine-protein kinase Src, MESH : Carcinoma, Hepatocellular, Adult, STAT3 Transcription Factor, Carcinoma, Hepatocellular, MESH : Interleukin-6, MESH : Models, Molecular, MESH : Male, Immunology, Active Transport, Cell Nucleus, Biology, IFN, Adenoma, Liver Cell, gp130, 03 medical and health sciences, MESH : Adenoma, Liver Cell, MESH : Protein Structure, Quaternary, Cell Line, Tumor, medicine, Humans, MESH : Middle Aged, Protein Structure, Quaternary, MESH : Active Transport, Cell Nucleus, Aged, 030304 developmental biology, MESH : Signal Transduction, IL-6, Base Sequence, MESH : Cell Line, Tumor, Interleukin-6, MESH : Humans, Brief Definitive Report, beta-catenin, digestive system diseases, STAT protein, Inflammatory Hepatocellular Adenoma, Cancer research, Tyrosine, MESH : src-Family Kinases, MESH : Base Sequence, Mutant Proteins, Carcinogenesis
Abstract

Somatic STAT3 mutations present in a subset of inflammatory hepatocellular adenomas result in the generation of constitutively active STAT3 proteins that homodimerize independently of IL-6 stimulation., Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumors. 60% of these tumors have IL-6 signal transducer (IL6ST; gp130) mutations that activate interleukin 6 (IL-6) signaling. Here, we report that 12% of IHCA subsets lacking IL6ST mutations harbor somatic signal transducer and activator of transcription 3 (STAT3) mutations (6/49). Most of these mutations are amino acid substitutions in the SH2 domain that directs STAT3 dimerization. In contrast to wild-type STAT3, IHCA STAT3 mutants constitutively activated the IL-6 signaling pathway independent of ligand in hepatocellular cells. Indeed, the IHCA STAT3 Y640 mutant homodimerized independent of IL-6 and was hypersensitive to IL-6 stimulation. This was associated with phosphorylation of tyrosine 705, a residue required for IL-6–induced STAT3 activation. Silencing or inhibiting the tyrosine kinases JAK1 or Src, which phosphorylate STAT3, impaired constitutive activity of IHCA STAT3 mutants in hepatocellular cells. Thus, we identified for the first time somatic STAT3 mutations in human tumors, revealing a new mechanism of recurrent STAT3 activation and underscoring the role of the IL-6–STAT3 pathway in benign hepatocellular tumorigenesis.

Published
2011
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2. Ceftazidime-hydrolysing -lactamase OXA-145 with impaired hydrolysis of penicillins in Pseudomonas aeruginosa

Author

Barbara Dehecq, Mélanie Colomb, Djalal Meziane-Cherif, Olivier Belmonte, Patrick Plésiat, Didier Hocquet, Patrice Courvalin, Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Agents antibactériens, Institut Pasteur [Paris] (IP), Agents pathogènes et inflammation - UFC (EA 4266) (API), Université de Franche-Comté (UFC), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Institut Pasteur [Paris], Agents pathogènes et inflammation - UFC (EA 4266) ( API ), Université de Franche-Comté ( UFC ), and Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE)

Subjects
MESH : Escherichia coli, MESH: Sequence Analysis, DNA, MESH: Ceftazidime, MESH : Mutant Proteins, Cephalosporin, MESH: beta-Lactamases, Ceftazidime, MESH : Ceftazidime, Polymerase Chain Reaction, MESH: Mutant Proteins, MESH : Isoelectric Point, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, polycyclic compounds, MESH : DNA, Bacterial, Pharmacology (medical), MESH : Anti-Bacterial Agents, Cloning, Molecular, MESH : Polymerase Chain Reaction, Sequence Deletion, chemistry.chemical_classification, MESH: Microbial Sensitivity Tests, 0303 health sciences, MESH: Kinetics, integumentary system, MESH: Escherichia coli, Hydrolysis, Omega loop, MESH : beta-Lactamases, MESH : Pseudomonas aeruginosa, MESH: Sequence Deletion, MESH : Mutagenesis, Site-Directed, Anti-Bacterial Agents, Amino acid, MESH: Mutagenesis, Site-Directed, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, Biochemistry, Pseudomonas aeruginosa, MESH: Pseudomonas aeruginosa, MESH : Penicillins, MESH : Kinetics, MESH: Hydrolysis, medicine.drug, DNA, Bacterial, Microbiology (medical), MESH : Cloning, Molecular, medicine.drug_class, Microbial Sensitivity Tests, Penicillins, Biology, beta-Lactamases, 03 medical and health sciences, MESH : Hydrolysis, MESH: Penicillins, MESH: Anti-Bacterial Agents, Escherichia coli, medicine, Humans, Nitrocefin, MESH: Cloning, Molecular, Isoelectric Point, Monobactams, 030304 developmental biology, Pharmacology, MESH: Humans, MESH: Isoelectric Point, 030306 microbiology, MESH : Sequence Deletion, MESH : Humans, MESH: Polymerase Chain Reaction, Sequence Analysis, DNA, biochemical phenomena, metabolism, and nutrition, MESH: DNA, Bacterial, Penicillin, Kinetics, chemistry, Mutagenesis, Site-Directed, bacteria, Mutant Proteins, MESH : Microbial Sensitivity Tests, MESH : Sequence Analysis, DNA
Abstract

International audience; OBJECTIVES: To describe a novel extended-spectrum oxacillinase, named OXA-145, differing from narrow-spectrum OXA-35 (from the OXA-10 group) by deletion of residue Leu-165. The genetic environment of bla(OXA-145) and the biochemical properties of OXA-145 are reported. We also assessed the impact of the Leu-165 deletion on the hydrolysis spectrum of the ancestor OXA-10. METHODS: Extended-spectrum β-lactamase OXA-145 was identified in the multidrug-resistant clinical Pseudomonas aeruginosa 08-056, and characterized by isoelectric focusing, PCR and DNA sequencing. Antibiotic susceptibility tests were performed by agar dilution. The resistance profiles conferred by cloned bla(OXA-10), bla(OXA-35), bla(OXA-145) and a bla(OXA-10) derivative obtained by site-directed mutagenesis were determined in Escherichia coli. Kinetic parameters of OXA-35 and OXA-145 were established after purification of His-tagged proteins. RESULTS: The sequence of OXA-145, encoded by a class 1 integron-borne gene in strain 08-056, differed from that of narrow-spectrum penicillinase OXA-35 by a single amino acid deletion (Leu-165) located in the highly conserved omega loop. Deletion of Leu-165 from OXA-35 (yielding OXA-145) or OXA-10 (the progenitor of OXA-35) extended the hydrolysis spectrum to third-generation cephalosporins and to monobactams, while reducing that for penicillins. OXA-145 showed biphasic hydrolysis curves for all the substrates tested. Its activity against nitrocefin was 10-fold higher in the presence of sodium hydrogen carbonate. CONCLUSIONS: OXA-145 is a new extended-spectrum β-lactamase from the OXA-10 group. The deletion of Leu-165 is responsible for a shift in the hydrolysis spectrum from penicillins to third-generation cephalosporins, as well as monobactams. The loss of penicillin hydrolysis was due to a non-carboxylated Lys-73.

Published
2011
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3. DCC constrains tumour progression via its dependence receptor activity

Author

Loraine Jarrosson-Wuilleme, Jean-Yves Scoazec, Guillaume Chazot, Marie Castets, Laura Broutier, Yann Molin, Armelle Paquet, Patrick Mehlen, Nicolas Gadot, Laetitia Mazelin, Marie Brevet, Agnès Bernet, Puisieux, Alain, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Anipath, UFR Médecine Lyon-RTH Laennec, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Deleted in Colorectal Cancer, MESH : Mutant Proteins, MESH : Receptors, Cell Surface, Apoptosis, Dependence receptor, law.invention, MESH : Adenocarcinoma, Mice, MESH: Mutant Proteins, 0302 clinical medicine, law, Netrin, MESH : Intestinal Neoplasms, MESH: Animals, MESH: Gene Silencing, Receptor, Cells, Cultured, Cancer, MESH: Receptors, Cell Surface, 0303 health sciences, MESH: Genes, APC, Multidisciplinary, MESH : Tumor Suppressor Proteins, Genomics, Netrin-1, DCC Receptor, 3. Good health, 030220 oncology & carcinogenesis, Caspases, MESH: HEK293 Cells, Disease Progression, MESH: Disease Progression, MESH : Mutation, MESH: Cells, Cultured, Genes, APC, MESH: Mutation, Context (language use), Receptors, Cell Surface, Biology, Adenocarcinoma, MESH : Nerve Growth Factors, 03 medical and health sciences, MESH : Mice, MESH : Cells, Cultured, MESH : Fibroblasts, MESH : Gene Silencing, Intestinal Neoplasms, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene silencing, Animals, Humans, MESH: Tumor Suppressor Proteins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene Silencing, Nerve Growth Factors, MESH: Intestinal Neoplasms, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Humans, MESH: Caspases, MESH: Nerve Growth Factors, Tumor Suppressor Proteins, MESH: Apoptosis, MESH : Humans, fungi, MESH: Adenocarcinoma, MESH : Disease Progression, Fibroblasts, MESH : Disease Models, Animal, MESH : HEK293 Cells, Disease Models, Animal, MESH : Genes, APC, HEK293 Cells, MESH: Fibroblasts, Immunology, Mutation, Cancer research, Suppressor, Mutant Proteins, MESH : Animals, MESH : Caspases, MESH: Disease Models, Animal, MESH : Apoptosis
Abstract

International audience; The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers and, by functioning as a dependence receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis.

Published
2012
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4. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease

Author

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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