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J Clin Invest. 2018 Jul 2;128(7):3071-3087. doi: 10.1172/JCI98164. Epub 2018 Jun 11.

Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency.

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Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm UMR 1163, Paris, France.
Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland, USA.
University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris, France.
Centre National de la Recherche Scientifique UMR 7590, Sorbonne Universities, University Pierre et Marie Curie-Paris 6-MNHN-IRD-IUC, Paris, France.
Department of Paediatric Haematology-Oncology, La Timone Hospital, Marseille, France.
Assistance Publique - Hôpitaux de Marseille (APHM) Hôpital Timone Enfants, Service d'Immunologie - Marseille Immunopôle, Marseille, France.
Aix Marseille University, APHM, CNRS, Inserm, Centre d'Immunologie de Marseille-Luminy (CIML), Hôpital Timone Enfants, Service d'Immunologie - Marseille Immunopôle, Marseille, France.
Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Pediatric Immunology and Rheumatology, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
University Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Inserm 1151 and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (APHP), Necker-Enfants Malades Hospital, Paris, France.
Levine Children's Hospital, Carolinas Healthcare System, Charlotte, North Carolina, USA.
Department of Pediatrics, Division of Rheumatology, Medical College of Wisconsin, Madison, Wisconsin, USA.
Hematology section, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland, USA.
Division of Human Genetics and Division of Immune Deficiency and Bone Marrow Transplant, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
University of South Carolina School of Medicine, Columbia, South Carolina, USA.
Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, APHP, Paris, France.
Collège de France, Paris, France.
Centre d'Etude des Déficits Immunitaires, Necker-Enfants Malades Hospital, APHP, Paris, France.


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.


Genetics; Immunology; Monocytes; Monogenic diseases; T cells

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