• Akihiro Hoshino, Satoshi Okada, Kenichi Yoshida, Naonori Nishida, Yusuke Okuno, Hiroo Ueno, Motoi Yamashita, Tsubasa Okano, Miyuki Tsumura, Shiho Nishimura, Sonoko Sakata, Masao Kobayashi, Haruna Nakamura, Junji Kamizono, Kanako Mitsui-Sekinaka, Takuya Ichimura, Shouichi Ohga, Yozo Nakazawa, Masatoshi Takagi, Kohsuke Imai, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Seishi Ogawa, Seiji Kojima, Shigeaki Nonoyama, Tomohiro Morio, and Hirokazu Kanegane.
• 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.
• J. Allergy Clin. Immunol. 2017 Jul 1; 140 (1): 223-231.

BackgroundIkaros, 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.ObjectiveWe sought to describe the clinical and immunologic phenotypes of Japanese patients with heterozygous IKZF1 mutations.MethodsWe 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.ResultsNine 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.ConclusionsGermline heterozygous IKZF1 mutations cause dysgammaglobulinemia; hematologic abnormalities, including B-cell defect; and autoimmune diseases.Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

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