title: An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex.
abstract: BACKGROUND
  Immunoglobulin class-switch recombination defects (CSR-D) are rare primary immunodeficiencies characterized by impaired production of switched immunoglobulin isotypes and normal or elevated IgM levels. They are caused by impaired T:B cooperation or intrinsic B cell defects. However, many immunoglobulin CSR-Ds are still undefined at the molecular level.
  
  
  OBJECTIVE
  This study's objective was to delineate new causes of immunoglobulin CSR-Ds and thus gain further insights into the process of immunoglobulin class-switch recombination (CSR).
  
  
  METHODS
  Exome sequencing in 2 immunoglobulin CSR-D patients identified variations in the INO80 gene. Functional experiments were performed to assess the function of INO80 on immunoglobulin CSR.
  
  
  RESULTS
  We identified recessive, nonsynonymous coding variations in the INO80 gene in 2 patients affected by defective immunoglobulin CSR. Expression of wild-type INO80 in patients' fibroblastic cells corrected their hypersensitivity to high doses of γ-irradiation. In murine CH12-F3 cells, the INO80 complex accumulates at Sα and Eμ regions of the IgH locus, and downregulation of INO80 as well as its partners Reptin and Pontin impaired CSR. In addition, Reptin and Pontin were shown to interact with activation-induced cytidine deaminase. Finally, an abnormal separation of sister chromatids was observed upon INO80 downregulation in CH12-F3 cells, pinpointing its role in cohesin activity.
  
  
  CONCLUSIONS
  INO80 deficiency appears to be associated with defective immunoglobulin CSR. We propose that the INO80 complex modulates cohesin function that may be required during immunoglobulin switch region synapsis.
authors.affiliation: INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
authors.affiliation: Laboratory of Molecular Immunology, Howard Hughes Medical Institute, the Rockefeller University, New York, NY.
authors.forename: Michela
authors.initials: M
authors.lastname: Di Virgilio
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: International Agency for Research on Cancer, F-69008 Lyon, Lyon, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Cuenin
authors.affiliation: Center for Primary Immunodeficiencies, Hôpital Necker Enfants Malades, F-75015 Paris, Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Forveille
authors.affiliation: INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: Marie-Céline
authors.initials: MC
authors.lastname: Deau
authors.affiliation: Laboratory of Molecular Immunology, Howard Hughes Medical Institute, the Rockefeller University, New York, NY.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: McBride
authors.affiliation: Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Laboratory of Molecular Immunology, Howard Hughes Medical Institute, the Rockefeller University, New York, NY.
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free London NHS Foundation Tust, London, United Kingdom.
authors.forename: Suranjith
authors.initials: S
authors.lastname: Seneviratne
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free London NHS Foundation Tust, London, United Kingdom; Centre of Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, D-79106 Freiburg, Freiburg, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.affiliation: Ege University Faculty of Medicine, Department of Pediatric Immunology, 35100 Bornova, Izmir, Turkey.
authors.forename: Necil
authors.initials: N
authors.lastname: Kutukculer
authors.affiliation: International Agency for Research on Cancer, F-69008 Lyon, Lyon, France.
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.affiliation: INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France; Department of Biotherapy, AP-HP Hôpital Necker Enfants Malades, F-75015 Paris, Paris, France; Clinical Investigation Center (CIC)-Biotherapy GHU Ouest, INSERM-APHP (Assistance Publique des Hôpitaux de Paris), Paris, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana
authors.affiliation: Department of Pediatrics, McGill University and McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Laboratory of Molecular Immunology, Howard Hughes Medical Institute, the Rockefeller University, New York, NY.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France; Department of Immunology and Hematology, Hôpital Necker Enfants Malades, F-75015 Paris, Paris, France; Collège de France, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: INSERM UMR 1163, The Human Lymphohematopoiesis Laboratory, Imagine Institute, Paris, France; Paris Descartes Sorbonne Paris Cité University, Imagine Institute, Paris, France; Department of Immunology and Hematology, Hôpital Necker Enfants Malades, F-75015 Paris, Paris, France. Electronic address: anne.durandy@inserm.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D015321:Gene Rearrangement; D014644:Genetic Variation; D006801:Humans; D017578:Immunoglobulin Class Switching; D007132:Immunoglobulin Isotypes / Q000235:genetics; D007134:Immunoglobulin Switch Region; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D021381:Protein Transport; D000097722:Cohesins
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D007132:Immunoglobulin Isotypes; D000097722:Cohesins; C524421:INO80 protein, human; C486549:RUVBL1 protein, human; C122079:RUVBL2 protein, human
keywords: CSR synapse; Chromatin remodeling; class-switch recombination defect; cohesin