Akihiro Hoshino1, Satoshi Okada2, Kenichi Yoshida3, Naonori Nishida4, Yusuke Okuno5, Hiroo Ueno3, Motoi Yamashita6, Tsubasa Okano6, Miyuki Tsumura2, Shiho Nishimura2, Sonoko Sakata2, Masao Kobayashi2, Haruna Nakamura7, Junji Kamizono8, Kanako Mitsui-Sekinaka9, Takuya Ichimura10, Shouichi Ohga10, Yozo Nakazawa11, Masatoshi Takagi12, Kohsuke Imai12, Yuichi Shiraishi13, Kenichi Chiba13, Hiroko Tanaka14, Satoru Miyano15, Seishi Ogawa3, Seiji Kojima5, Shigeaki Nonoyama9, Tomohiro Morio6, Hirokazu Kanegane16. 1. 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. 2. Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan. 3. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 4. Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. 5. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan. 6. 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. 7. Department of Pediatrics, National Mie Hospital, Tsu, Japan. 8. Department of Pediatrics, Kitakyushu City Yahata Hospital, Kitakyushu, Japan. 9. Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan. 10. Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Ube, Japan. 11. Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan. 12. Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. 13. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 14. Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan. 15. 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. 16. 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.
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.
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.
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