Ebru Yilmaz1, Hye S Kuehn2, Eda Odakir1, Julie E Niemela2, Alper Ozcan1, Ahmet Eken3,4, Meino Rohlfs5, Murat Cansever6, Veysel Gok1, Firdevs Aydin1, Musa Karakukcu1, Fabian Hauck5,7, Christoph Klein5,7, Ekrem Unal1,4, Sergio D Rosenzweig2, Turkan Patiroglu1,6. 1. Department of Pediatrics, Division of Pediatric Hematology and Oncology & Pediatric HSCT Unit. 2. Department of Laboratory Medicine, Immunology Service, National Institutes of Health Clinical Center, Bethesda, MD. 3. Departments of Medical Biology. 4. Molecular Biology and Genetics Department, Gevher Nesibe Genom and Stem Cell Institution, Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey. 5. Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München. 6. Pediatrics, Division of Pediatric Immunology, Faculty of Medicine. 7. German Centre for Infection Research (DZIF), Munich, Germany.
Abstract
OBJECTIVE: Mutations in IKZF1, which encodes Ikaros family zinc finger 1 (IKAROS) transcription factor, are associated with recurrent infections, cytopenia, autoimmune diseases, and hematologic malignancies. Diverse clinical phenotypes resulting from IKZF1 mutations include pulmonary fungal infections, cytopenia, autoimmune hemolytic anemia (AIHA), and malignancies. In this study, we aimed to assess the DNA-binding ability and pericentromeric (PC) localization of a variant of IKZF discovered in a patient. MATERIALS AND METHODS: DNA-binding ability of a pathogenic IKZF variant was tested using electrophoretic mobility shift assay and PC localization of the variant was assessed by immunofluorescent microscopy in NIH3T3 cells. RESULTS: Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described. DNA studies revealed a heterozygous missense variant (IKZF1 NM_006060 c.427C>T; p.R143W). Cotransfection studies revealed that mutant R143W has a partial dominant-negative effect over PC targeting and DNA binding. CONCLUSIONS: IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immunodeficiency, and pancytopenia are observed.
OBJECTIVE: Mutations in IKZF1, which encodes Ikaros family zinc finger 1 (IKAROS) transcription factor, are associated with recurrent infections, cytopenia, autoimmune diseases, and hematologic malignancies. Diverse clinical phenotypes resulting from IKZF1 mutations include pulmonary fungal infections, cytopenia, autoimmune hemolytic anemia (AIHA), and malignancies. In this study, we aimed to assess the DNA-binding ability and pericentromeric (PC) localization of a variant of IKZF discovered in a patient. MATERIALS AND METHODS: DNA-binding ability of a pathogenic IKZF variant was tested using electrophoretic mobility shift assay and PC localization of the variant was assessed by immunofluorescent microscopy in NIH3T3 cells. RESULTS: Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described. DNA studies revealed a heterozygous missense variant (IKZF1 NM_006060 c.427C>T; p.R143W). Cotransfection studies revealed that mutant R143W has a partial dominant-negative effect over PC targeting and DNA binding. CONCLUSIONS: IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immunodeficiency, and pancytopenia are observed.
Authors: David Boutboul; Hye Sun Kuehn; Zoé Van de Wyngaert; Julie E Niemela; Isabelle Callebaut; Jennifer Stoddard; Christelle Lenoir; Vincent Barlogis; Catherine Farnarier; Frédéric Vely; Nao Yoshida; Seiji Kojima; Hirokazu Kanegane; Akihiro Hoshino; Fabian Hauck; Ludovic Lhermitte; Vahid Asnafi; Philip Roehrs; Shaoying Chen; James W Verbsky; Katherine R Calvo; Ammar Husami; Kejian Zhang; Joseph Roberts; David Amrol; John Sleaseman; Amy P Hsu; Steven M Holland; Rebecca Marsh; Alain Fischer; Thomas A Fleisher; Capucine Picard; Sylvain Latour; Sergio D Rosenzweig Journal: J Clin Invest Date: 2018-06-11 Impact factor: 14.808
Authors: N Yoshida; H Sakaguchi; H Muramatsu; Y Okuno; C Song; S Dovat; A Shimada; M Ozeki; H Ohnishi; T Teramoto; T Fukao; N Kondo; Y Takahashi; K Matsumoto; K Kato; S Kojima Journal: Leukemia Date: 2017-01-18 Impact factor: 11.528