Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells
| Autor: | Gaël Ménasché, Sylvain Latour, Françoise Le Deist, Nizar Mahlaoui, Geneviève de Saint Basile, Astrid Cariou, Musa Alharbi, Gehad ElGhazali, Capucine Picard, Fahad Al-Manjomi, Andrew R. Gennery, Nathalie Prince, Ulrich Blank, Marjorie Côte, Agathe Burgess, Patrick Nitschke, Abdullah A. Alangari, Catherine Schaffner, Alain Fischer, Mickaël M. Ménager |
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| Přispěvatelé: | 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pediatrics, King Faysal Hospital and Research center, Newcastle University [Newcastle], Langues, Littératures, Linguistique des universités d'Angers et du Mans (3L.AM), Le Mans Université (UM)-Université d'Angers (UA), Service de Bioinformatique, Université Paris Descartes - Paris 5 (UPD5), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Langues, Littératures, Linguistique des Universités d'Angers et du Mans (3L.AM), Ménasché, Gaël |
| Rok vydání: | 2009 |
| Předmět: |
Male
Models Molecular [SDV]Life Sciences [q-bio] Consanguinity 0302 clinical medicine Cytotoxic T cell Syntaxin Child 0303 health sciences [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology Qa-SNARE Proteins Homozygote General Medicine Familial Hemophagocytic Lymphohistiocytosis Pedigree Killer Cells Natural [SDV] Life Sciences [q-bio] STX11 [SDV.IMM]Life Sciences [q-bio]/Immunology Female Research Article Adolescent [SDV.IMM] Life Sciences [q-bio]/Immunology Molecular Sequence Data Mutation Missense Genes Recessive [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Exocytosis Lymphohistiocytosis Hemophagocytic STXBP2 Deficiency Young Adult 03 medical and health sciences Munc18 Proteins [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics Humans UNC13D Amino Acid Sequence [SDV.BC] Life Sciences [q-bio]/Cellular Biology 030304 developmental biology [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics Base Sequence Sequence Homology Amino Acid Infant Molecular biology Introns Amino Acid Substitution Perforin Cancer research biology.protein Ectopic expression RNA Splice Sites [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology 030215 immunology |
| Zdroj: | Journal of Clinical Investigation Journal of Clinical Investigation, American Society for Clinical Investigation, 2009, 119 (12), pp.3765-3773. ⟨10.1172/JCI40732⟩ Journal of Clinical Investigation, 2009, 119 (12), pp.3765-3773. ⟨10.1172/JCI40732⟩ |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci40732 |
| Popis: | International audience; Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous autosomal recessive immune disorder characterized by the occurrence of uncontrolled activation of lymphocytes and macrophages infiltrating multiple organs. Disease-causing mutations in the perforin (PRF1; also known as FHL2), Munc13-4 (UNC13D; also known as FHL3), and syntaxin-11 (STX11; also known as FHL4) genes have been identified in individuals with FHL. These genes all encode proteins involved in the cytotoxic activity of lymphocytes. Here, we show that the gene encoding syntaxin-binding protein 2 (Munc18-2; official gene symbol STXBP2) is mutated in another subset of patients with FHL (designated by us as "FHL5"). Lymphoblasts isolated from these patients had strongly decreased STXBP2 protein expression, and NK cells exhibited impaired cytotoxic granule exocytosis, a defect that could be overcome by ectopic expression of wild-type STXBP2. Furthermore, we provide evidence that syntaxin-11 is the main partner of STXBP2 in lymphocytes, as its expression required the presence of STXBP2. Our work shows that STXBP2 deficiency causes FHL5. These data indicate that STXBP2 is required at a late step of the secretory pathway for the release of cytotoxic granules by binding syntaxin 11, another component of the intracellular membrane fusion machinery. |
| Databáze: | OpenAIRE |
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