Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency
In: Journal of Clinical Investigation Journal of Clinical Investigation, American Society for Clinical Investigation, 2018, 128 (7), pp.3071-3087. ⟨10.1172/JCI98164⟩ Journal of Clinical Investigation, 2018, 128 (7), pp.3071-3087. ⟨10.1172/JCI98164⟩; (2018-07-02)
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Zugriff:
International audience; Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.
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Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency
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Autor/in / Beteiligte Person: | Niemela, Julie E. ; Roberts, Joseph L. ; Calvo, Katherine R. ; Hoshino, Akihiro ; Rosenzweig, Sergio D. ; Sleaseman, John ; Callebaut, Isabelle ; Farnarier, Catherine ; Husami, Ammar ; Chen, Shaoying ; Hsu, Amy P. ; Fischer, Alain ; Picard, Capucine ; Vély, Frédéric ; Kanegane, Hirokazu ; Latour, Sylvain ; Amrol, David ; Kojima, Seiji ; Asnafi, Vahid ; Marsh, Rebecca A. ; Holland, Steven M. ; Lenoir, Christelle ; Verbsky, James W. ; Barlogis, Vincent ; Boutboul, David ; Lhermitte, Ludovic ; Zhang, Kejian ; Hye Sun Kuehn ; Fleisher, Thomas A. ; Yoshida, Nao ; Roehrs, Philip ; Zoé Van de Wyngaert ; Stoddard, Jennifer ; Hauck, Fabian ; Service d'Immunopathologie [Hôpital Saint-Louis, Paris] ; Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP) ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) ; Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland ; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm UMR 1163 ; Institut de minéralogie et de physique des milieux condensés (IMPMC) ; Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-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) ; Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM] ; Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE) ; Service de Chirurgie ; Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION) ; Service d'Immunologie [AP-HM] ; Hôpital de la Conception [CHU - APHM] (LA CONCEPTION) ; Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya ; Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya ; Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo ; Department of Pediatric Immunology and Rheumatology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Munich ; CHU Necker - Enfants Malades [AP-HP] ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) ; Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)) ; Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; Levine Children's Hospital, Carolinas Healthcare System, Charlotte, North Carolina ; Department of Pediatrics, Division of Rheumatology, Medical College of Wisconsin, Madison, Wisconsin ; Hematology section, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland ; Division of Human Genetics and Division of Immune Deficiency and Bone Marrow Transplant, Cincinnati Children's Hospital, Cincinnati, Ohio ; University of South Carolina School of Medicine, Columbia, South Carolina ; Department of Pediatrics, Duke University Medical Center, Durham, North Carolina ; Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland ; Division of Human Genetics and Division of Immune Deficiency and Bone Marrow Transplant, Cincinnati Children's Hospital, Cincinnati ; Developpement Normal et Pathologique du Système Immunitaire ; Chaire Médecine expérimentale (A. Fischer) ; Collège de France (CdF (institution)) ; Centre d'étude des Déficits Immunitaires ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP] ; University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris ; Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC) ; Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) ; Assistance Publique - Hôpitaux de Marseille (APHM) Hôpital Timone Enfants, Service d'Immunologie - Marseille Immunopôle, Marseille ; Centre d'Immunologie de Marseille - Luminy (CIML) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU) ; Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, APHP, Paris ; Centre d'Etude des Déficits Immunitaires, Necker-Enfants Malades Hospital, APHP, Paris ; Université Paris Diderot - Paris 7 (UPD7)-CHU Saint Louis [APHP] ; Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ) ; Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ) ; Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP] ; Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS) ; Ludwig-Maximilians-Universität München (LMU) ; School of Medicine [University of South Carolina] ; University of South Carolina [Columbia] ; Collège de France - Chaire Médecine expérimentale (A. Fischer) |
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Quelle: | Journal of Clinical Investigation Journal of Clinical Investigation, American Society for Clinical Investigation, 2018, 128 (7), pp.3071-3087. ⟨10.1172/JCI98164⟩ Journal of Clinical Investigation, 2018, 128 (7), pp.3071-3087. ⟨10.1172/JCI98164⟩; (2018-07-02) |
Veröffentlichung: | HAL CCSD, 2018 |
Medientyp: | unknown |
ISSN: | 0021-9738 (print) |
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