title: Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations.
abstract: BACKGROUND
  Ikaros, which is encoded by IKZF1, is a transcriptional factor that play a critical role in hematopoiesis. Somatic IKZF1 alterations are known to be involved in the pathogenesis of leukemia in human subjects. Recently, immunodeficiency caused by germline IKZF1 mutation has been described.
  
  
  OBJECTIVE
  We sought to describe the clinical and immunologic phenotypes of Japanese patients with heterozygous IKZF1 mutations.
  
  
  METHODS
  We performed whole-exome sequencing in patients from a dysgammaglobulinemia or autoimmune disease cohort and used a candidate gene approach in 4 patients. Functional and laboratory studies, including detailed lymphopoiesis/hematopoiesis analysis in the bone marrow, were performed.
  
  
  RESULTS
  Nine patients from 6 unrelated families were identified to have heterozygous germline mutations in IKZF1. Age of onset was 0 to 20 years (mean, 7.4 years). Eight of 9 patients presented with dysgammaglobulinemia accompanied by B-cell deficiency. Four of 9 patients had autoimmune disease, including immune thrombocytopenic purpura, IgA vasculitis, and systemic lupus erythematosus. Nonautoimmune pancytopenia was observed in 1 patient. All of the mutant Ikaros protein demonstrated impaired DNA binding to the target sequence and abnormal diffuse nuclear localization. Flow cytometric analysis of bone marrow revealed reduced levels of common lymphoid progenitors and normal development of pro-B to pre-B cells.
  
  
  CONCLUSIONS
  Germline heterozygous IKZF1 mutations cause dysgammaglobulinemia; hematologic abnormalities, including B-cell defect; and autoimmune diseases.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; Department of Pediatrics and Developmental Biology, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hoshino
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Naonori
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Ueno
authors.affiliation: Department of Pediatrics and Developmental Biology, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Department of Pediatrics and Developmental Biology, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Okano
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tsumura
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Sonoko
authors.initials: S
authors.lastname: Sakata
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics, National Mie Hospital, Tsu, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Pediatrics, Kitakyushu City Yahata Hospital, Kitakyushu, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kamizono
authors.affiliation: Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Mitsui-Sekinaka
authors.affiliation: Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ichimura
authors.affiliation: Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Shouichi
authors.initials: S
authors.lastname: Ohga
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Nakazawa
authors.affiliation: Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.affiliation: Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Imai
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kojima
authors.affiliation: Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.affiliation: Department of Pediatrics and Developmental Biology, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.affiliation: Department of Pediatrics and Developmental Biology, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. Electronic address: hkanegane.ped@tmd.ac.jp.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
mesh_terms: D000293:Adolescent; D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D002648:Child; D005260:Female; D018095:Germ-Line Mutation; D006402:Hematologic Diseases / Q000235:genetics* / Q000276:immunology; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology; D055815:Young Adult
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor
keywords: Acute lymphoblastic leukemia; B-cell deficiency; DNA binding; IKZF1; Ikaros; autoimmune disease; common lymphoid progenitor; dysgammaglobulinemia; germline mutation; nuclear localization