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5 results on '"MESH : Genes, Dominant"'

1. Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin

Author

Jean-Michel Goujon, Mathieu Boimard, Corinne Lacombe, Violaine Planté-Bordeneuve, Philip N. Hawkins, Monica Stoppini, Julie A. Vrana, Mark B. Pepys, Guy Touchard, Vittorio Bellotti, Riccardo Porcari, Thierry Maisonobe, Franck Bridoux, Sophie Valleix, Julian D. Gillmore, Ahmet Dogan, Martino Bolognesi, Jason D. Theis, Pierre Lozeron, Sofia Giorgetti, Marc Delpech, Catherine Lacroix, Stefano Ricagno, David H. Adams, Brigitte Nedelec, Palma Mangione, Laboratoire de Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service de néphrologie - hémodialyse et transplantation rénale, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire d'anatomopathologie, Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ), Contrôle de la Réponse Immune B et des Lymphoproliférations ( CRIBL ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ), Université de Poitiers-Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Ischémie - Reperfusion en transplatation rénale, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
Male, MESH: Hydrogen-Ion Concentration, Proteome, MESH: Protein Structure, Quaternary, MESH : beta 2-Microglobulin, MESH : Diarrhea, MESH: Monitoring, Physiologic, 0302 clinical medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, Genes, Dominant, 0303 health sciences, MESH: Middle Aged, biology, Amyloidosis, MESH: Infant, Newborn, Fibrillogenesis, MESH : Genes, Dominant, General Medicine, Middle Aged, MESH : Amyloidosis, Familial, Pedigree, MESH: Glass, MESH: Proteome, MESH: Diarrhea, Sjogren's Syndrome, MESH : Glass, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Protein folding, MESH: beta 2-Microglobulin, MESH : Scalp, Amyloidosis, Familial, Diarrhea, medicine.medical_specialty, Amyloid, MESH: Pedigree, MESH : Male, MESH : Proteome, MESH : Infant, Newborn, Fibril, MESH: Scalp, 03 medical and health sciences, MESH : Hydrogen-Ion Concentration, MESH : Protein Structure, Quaternary, Internal medicine, medicine, Humans, MESH : Middle Aged, MESH: Fetal Blood, Protein Structure, Quaternary, 030304 developmental biology, MESH : Fetal Blood, MESH: Humans, Beta-2 microglobulin, business.industry, MESH : Humans, MESH : Monitoring, Physiologic, MESH: Electrodes, medicine.disease, MESH: Amyloidosis, Familial, In vitro, MESH: Male, Transthyretin, Endocrinology, MESH: Sjogren's Syndrome, MESH : Pedigree, biology.protein, MESH : Sjogren's Syndrome, beta 2-Microglobulin, business, MESH: Genes, Dominant, MESH: Female, 030217 neurology & neurosurgery, MESH : Electrodes
Abstract

International audience; We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant β(2)-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β(2)-microglobulin, the affected members of this kindred had normal renal function and normal circulating β(2)-microglobulin values. The Asp76Asn β(2)-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β(2)-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β(2)-microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.

Published
2012
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2. PAI-1 and functional blockade of SNAI1 in breast cancer cell migration

Author

José Palacios, Amparo Cano, Amandine Cartier-Michaud, Gema Moreno-Bueno, Elizabeth Fabre-Guillevin, Benoît Vallée, Michel Malo, Georgia Barlovatz-Meimon, Daniel A. Lawrence, Héctor Peinado, Cécile Charrière-Bertrand, Hôpital Européen Georges Pompidou [APHP] (HEGP), DYNAMIC, Informatique, Biologie Intégrative et Systèmes Complexes (IBISC), Université d'Évry-Val-d'Essonne (UEVE) - Centre National de la Recherche Scientifique (CNRS) - Université d'Évry-Val-d'Essonne (UEVE) - Centre National de la Recherche Scientifique (CNRS), Centre National d'Investigations Oncologiques (CNIO), CNIO, Laboratoire de recherche sur la croissance cellulaire, la réparation et la régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12) - Centre National de la Recherche Scientifique (CNRS), Servicio de Anatomia Patologica, Hospital Virgen del Rocío, Université d'Évry-Val-d'Essonne (UEVE) - Centre National de la Recherche Scientifique (CNRS) - Université d'Évry-Val-d'Essonne (UEVE) - Centre National de la Recherche Scientifique (CNRS) - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Spanish National Cancer Research Center (CNIO), Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitario Virgen del Rocío [Sevilla], and Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE)

Subjects
MESH : RNA, Messenger, MESH : Transcription Factors, MESH : Wound Healing, Fluorescent Antibody Technique, Snail, MESH : Breast Neoplasms, MESH: Cadherins, MESH: Plasminogen Activator Inhibitor 1, Metastasis, Immunoenzyme Techniques, chemistry.chemical_compound, 0302 clinical medicine, MESH : Tumor Cells, Cultured, Cell Movement, MESH: Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, MESH : Cell Movement, MESH : Female, Pseudopodia, Receptor, MESH: Cell Movement, MESH: Fluorescent Antibody Technique, Genes, Dominant, Oligonucleotide Array Sequence Analysis, Medicine(all), 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, MESH : Reverse Transcriptase Polymerase Chain Reaction, Cell migration, MESH : Urokinase-Type Plasminogen Activator, MESH: Transcription Factors, MESH : Genes, Dominant, Cadherins, 3. Good health, MESH : Oligonucleotide Array Sequence Analysis, 030220 oncology & carcinogenesis, Plasminogen activator inhibitor-1, Female, MESH : Cadherins, Research Article, MESH : Plasminogen Activator Inhibitor 1, Breast Neoplasms, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Urokinase-Type Plasminogen Activator, MESH: Gene Expression Profiling, 03 medical and health sciences, MESH : Immunoenzyme Techniques, biology.animal, Plasminogen Activator Inhibitor 1, medicine, Humans, RNA, Messenger, MESH: Tumor Cells, Cultured, MESH: Immunoenzyme Techniques, Cell adhesion, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: RNA, Messenger, 030304 developmental biology, Wound Healing, MESH: Humans, Gene Expression Profiling, MESH : Gene Expression Profiling, MESH : Humans, Cancer, medicine.disease, Urokinase-Type Plasminogen Activator, Molecular biology, MESH: Wound Healing, MESH : Fluorescent Antibody Technique, chemistry, MESH: Pseudopodia, MESH: Oligonucleotide Array Sequence Analysis, SNAI1, MESH : Pseudopodia, Cancer research, Snail Family Transcription Factors, MESH: Genes, Dominant, MESH: Female, MESH: Breast Neoplasms, Transcription Factors
Abstract

International audience; INTRODUCTION: Snail, a family of transcriptional repressors implicated in cell movement, has been correlated with tumour invasion. The Plasminogen Activation (PA) system, including urokinase plasminogen activator (uPA), its receptor and its inhibitor, plasminogen activator inhibitor type 1(PAI-1), also plays a key role in cancer invasion and metastasis, either through proteolytic degradation or by non-proteolytic modulation of cell adhesion and migration. Thus, Snail and the PA system are both over-expressed in cancer and influence this process. In this study we aimed to determine if the activity of SNAI1 (a member of the Snail family) is correlated with expression of the PA system components and how this correlation can influence tumoural cell migration. METHODS: We compared the invasive breast cancer cell-line MDA-MB-231 expressing SNAI1 (MDA-mock) with its derived clone expressing a dominant-negative form of SNAI1 (SNAI1-DN). Expression of PA system mRNAs was analysed by cDNA microarrays and real-time quantitative RT-PCR. Wound healing assays were used to determine cell migration. PAI-1 distribution was assessed by immunostaining. RESULTS: We demonstrated by both cDNA microarrays and real-time quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts. After performing an in vitro wound-healing assay, we observed that SNAI1-DN cells migrate more slowly than MDA-mock cells and in a more collective manner. The blockade of SNAI1 activity resulted in the redistribution of PAI-1 in SNAI1-DN cells decorating large lamellipodia, which are commonly found structures in these cells. CONCLUSIONS: In the absence of functional SNAI1, the expression of PAI-1 transcripts is decreased, although the protein is redistributed at the leading edge of migrating cells in a manner comparable with that seen in normal epithelial cells.

Published
2008
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3. TLR3 deficiency in patients with herpes simplex encephalitis

Author

Vanessa Sancho-Shimizu, Armanda Casrouge, Pedro Romero, Flore Rozenberg, Capucine Picard, Anne Puel, Lluis Quintana-Murci, Asma Smahi, Bénédicte Héron, Frederic Geissmann, Lazaro Lorenzo, Joshua N. Leonard, Jean-Laurent Casanova, Matthias Titeux, Louis Vallée, Luis B. Barreiro, Eric Vivier, Céline Cognet, Horst von Bernuth, Alain Hovnanian, Gaelle Elain, Marc Tardieu, David J. Segal, Shen-Ying Zhang, Emmanuelle Jouanguy, Claire Hamilton, Cheng-Lung Ku, Pierre Lebon, Ariane Chapgier, Laurent Abel, Sophie Ugolini, Sabine Plancoulaine, Xin Xin Zhang, Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )

Subjects
Keratinocytes, MESH : Cell Line, viruses, MESH : Toll-Like Receptor 3, MESH : Immunity, Natural, Herpesvirus 1, Human, CD8-Positive T-Lymphocytes, MESH : Child, Preschool, medicine.disease_cause, 0302 clinical medicine, MESH : Interferons, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Interferons, MESH : Female, Genes, Dominant, MESH: Heterozygote, 0303 health sciences, Toll-like receptor, Multidisciplinary, MESH: Dendritic Cells, MESH : Keratinocytes, MESH: Encephalitis, Herpes Simplex, virus diseases, hemic and immune systems, MESH : Infant, MESH : Genes, Dominant, MESH: Toll-Like Receptor 3, MESH : CD8-Positive T-Lymphocytes, MESH: CD8-Positive T-Lymphocytes, MESH: Infant, MESH: Keratinocytes, 3. Good health, Killer Cells, Natural, MESH: Leukocytes, Mononuclear, MESH: Herpesvirus 1, Human, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Killer Cells, Natural, MESH : Mutation, Encephalitis, MESH : Poly I-C, MESH: Killer Cells, Natural, UNC93B1, Heterozygote, MESH : Heterozygote, MESH: Mutation, chemical and pharmacologic phenomena, Biology, MESH: Poly I-C, Virus, Herpesviridae, Cell Line, 03 medical and health sciences, Immunity, MESH : Fibroblasts, medicine, Humans, Alleles, 030304 developmental biology, MESH: Immunity, Natural, Innate immune system, MESH: Humans, MESH: Alleles, MESH: Child, Preschool, MESH : Humans, Infant, Dendritic Cells, Fibroblasts, medicine.disease, Virology, MESH : Herpesvirus 1, Human, Immunity, Innate, MESH : Encephalitis, Herpes Simplex, Toll-Like Receptor 3, MESH: Cell Line, MESH : Leukocytes, Mononuclear, Herpes simplex virus, Poly I-C, MESH: Fibroblasts, MESH : Dendritic Cells, Immunology, Mutation, Leukocytes, Mononuclear, Encephalitis, Herpes Simplex, Interferons, MESH: Genes, Dominant, MESH : Alleles, MESH: Female, 030215 immunology
Abstract

International audience; Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of TLR3.

Published
2007
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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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5. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome

Author

John R. Samples, M. Le Merrer, Gwenaëlle Collod-Béroud, N. Dagoneau, Maurice Godfrey, Catherine Boileau, Mary K. Wirtz, Valérie Cormier-Daire, Arnold Munnich, Robert J. Gorlin, Laurence Faivre, Handicaps génétiques de l'enfant ( Inserm U393 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Oral Science, University of Minnesota Health Sciences Center, Department of Ophthalmology, Casey Eye Institute, Oregon Health Sciences University, Department of Pediatrics and Munroe Center for Human Genetics, University of Nebraska Omaha, Génétique, chromosome et cancer, COLLOD-BEROUD, Gwenaëlle, Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minnesota Medical School, University of Minnesota System-University of Minnesota System, Oregon Health and Science University [Portland] (OHSU), University of Nebraska System-University of Nebraska System, and University of Nebraska [Omaha]

Subjects
Male, MESH: Extracellular Matrix Proteins, Reading Frames, Fibrillin-1, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH : Gene Deletion, MESH : Child, Preschool, Marfan Syndrome, Exon, 0302 clinical medicine, MESH : Child, MESH: Child, MESH : Microfilament Pro, MESH : Female, Eye Abnormalities, Child, 10. No inequality, Growth Disorders, Genetics (clinical), Genes, Dominant, Genetics, Extracellular Matrix Proteins, 0303 health sciences, Microfilament Proteins, Syndrome, MESH : Genes, Dominant, Middle Aged, MESH: Growth Disorders, MESH : Adult, MESH: Eye Abnormalities, Weill–Marchesani syndrome, Pedigree, Microspherophakia, Child, Preschool, Female, Fibrillin, Adult, MESH : Limb Deformities, Congenital, MESH: Abnormalities, Multiple, MESH: Limb Deformities, Congenital, Adolescent, MESH : Male, Short Report, Limb Deformities, Congenital, MESH: Microfilament Pro, Locus (genetics), Biology, Fibrillins, MESH: Marfan Syndrome, 03 medical and health sciences, MESH : Extracellular Matrix Proteins, MESH : Adolescent, MESH : Eye Abnormalities, medicine, Humans, Abnormalities, Multiple, MESH : Growth Disorders, Allele, 030304 developmental biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH : Marfan Syndrome, MESH : Abnormalities, Multiple, Genetic heterogeneity, Brachydactyly, MESH: Child, Preschool, MESH : Humans, MESH: Adult, medicine.disease, MESH: Male, eye diseases, MESH: Gene Deletion, 030221 ophthalmology & optometry, MESH: Genes, Dominant, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female, Gene Deletion
Abstract

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.

Published
2003

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