De novo variants in RHOBTB2 , an atypical Rho GTPase gene, cause epileptic encephalopathy

Human MutationVolume 39, Issue 8 p. 1070-1075 BRIEF REPORT De novo variants in RHOBTB2, an atypical Rho GTPase gene, cause epileptic encephalopathy Hazrat Belal, Hazrat Belal Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, Japan Hazrat Belal and Mitsuko Nakashima contributed equally to this work.Search for more papers by this authorMitsuko Nakashima, Mitsuko Nakashima Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, Japan Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, Japan Hazrat Belal and Mitsuko Nakashima contributed equally to this work.Search for more papers by this authorHiroshi Matsumoto, Hiroshi Matsumoto Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, JapanSearch for more papers by this authorKenji Yokochi, Kenji Yokochi Department of Pediatric Neurology, Seirei-Mikatahara General Hospital, Kita-ku, Hamamatsu, Japan Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Aotake-cho, Toyohashi, JapanSearch for more papers by this authorMariko Taniguchi-Ikeda, Mariko Taniguchi-Ikeda Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan Department of Clinical Genetics, Fujita Health University Hospital, Dengakugakubo, Toyoake, Aichi, JapanSearch for more papers by this authorKazushi Aoto, Kazushi Aoto Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, JapanSearch for more papers by this authorMohammed Badrul Amin, Mohammed Badrul Amin Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, Japan Enteric and Food Microbiology Laboratory, ICDDR,B, Dhaka, BangladeshSearch for more papers by this authorAzusa Maruyama, Azusa Maruyama Department of Neurology, Hyogo Prefectural Kobe Children's Hospital, Chuo-ku, Kobe, JapanSearch for more papers by this authorHiroaki Nagase, Hiroaki Nagase Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, JapanSearch for more papers by this authorTakeshi Mizuguchi, Takeshi Mizuguchi Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, JapanSearch for more papers by this authorSatoko Miyatake, Satoko Miyatake Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, JapanSearch for more papers by this authorNoriko Miyake, Noriko Miyake Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, JapanSearch for more papers by this authorKazumoto Iijima, Kazumoto Iijima Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, JapanSearch for more papers by this authorShigeaki Nonoyama, Shigeaki Nonoyama Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, JapanSearch for more papers by this authorNaomichi Matsumoto, Corresponding Author Naomichi Matsumoto naomat@yokohama-cu.ac.jp Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, Japan Correspondence Hirotomo Saitsu, Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431–3192, Japan. Email: hsaitsu@hama-med.ac.jp Naomichi Matsumoto, Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3–9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Email: naomat@yokohama-cu.ac.jpSearch for more papers by this authorHirotomo Saitsu, Corresponding Author Hirotomo Saitsu hsaitsu@hama-med.ac.jp orcid.org/0000-0003-0723-0960 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, Japan Correspondence Hirotomo Saitsu, Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431–3192, Japan. Email: hsaitsu@hama-med.ac.jp Naomichi Matsumoto, Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3–9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Email: naomat@yokohama-cu.ac.jpSearch for more papers by this author Hazrat Belal, Hazrat Belal Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, Japan Hazrat Belal and Mitsuko Nakashima contributed equally to this work.Search for more papers by this authorMitsuko Nakashima, Mitsuko Nakashima Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, Japan Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, Japan Hazrat Belal and Mitsuko Nakashima contributed equally to this work.Search for more papers by this authorHiroshi Matsumoto, Hiroshi Matsumoto Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, JapanSearch for more papers by this authorKenji Yokochi, Kenji Yokochi Department of Pediatric Neurology, Seirei-Mikatahara General Hospital, Kita-ku, Hamamatsu, Japan Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Aotake-cho, Toyohashi, JapanSearch for more papers by this authorMariko Taniguchi-Ikeda, Mariko Taniguchi-Ikeda Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan Department of Clinical Genetics, Fujita Health University Hospital, Dengakugakubo, Toyoake, Aichi, JapanSearch for more papers by this authorKazushi Aoto, Kazushi Aoto Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, JapanSearch for more papers by this authorMohammed Badrul Amin, Mohammed Badrul Amin Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, Japan Enteric and Food Microbiology Laboratory, ICDDR,B, Dhaka, BangladeshSearch for more papers by this authorAzusa Maruyama, Azusa Maruyama Department of Neurology, Hyogo Prefectural Kobe Children's Hospital, Chuo-ku, Kobe, JapanSearch for more papers by this authorHiroaki Nagase, Hiroaki Nagase Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, JapanSearch for more papers by this authorTakeshi Mizuguchi, Takeshi Mizuguchi Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, JapanSearch for more papers by this authorSatoko Miyatake, Satoko Miyatake Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, JapanSearch for more papers by this authorNoriko Miyake, Noriko Miyake Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, JapanSearch for more papers by this authorKazumoto Iijima, Kazumoto Iijima Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, JapanSearch for more papers by this authorShigeaki Nonoyama, Shigeaki Nonoyama Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, JapanSearch for more papers by this authorNaomichi Matsumoto, Corresponding Author Naomichi Matsumoto naomat@yokohama-cu.ac.jp Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, Japan Correspondence Hirotomo Saitsu, Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431–3192, Japan. Email: hsaitsu@hama-med.ac.jp Naomichi Matsumoto, Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3–9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Email: naomat@yokohama-cu.ac.jpSearch for more papers by this authorHirotomo Saitsu, Corresponding Author Hirotomo Saitsu hsaitsu@hama-med.ac.jp orcid.org/0000-0003-0723-0960 Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Higashi-ku, Hamamatsu, Japan Correspondence Hirotomo Saitsu, Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431–3192, Japan. Email: hsaitsu@hama-med.ac.jp Naomichi Matsumoto, Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3–9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Email: naomat@yokohama-cu.ac.jpSearch for more papers by this author First published: 16 May 2018 https://doi.org/10.1002/humu.23550Citations: 16 Communicated by Hamish S. Scott Funding information: Contract grant sponsors: Japan Agency for Medical Research and Development (JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18kk020500 and JP17ek0109297); Ministry of Education, Culture, Sports, Science, and Technology, Japan (24118007); Japan Society for the Promotion of Science (JP17H01539, JP16H05160, JP16H05357, JP15K10367, and JP17K10080); Japan Science and Technology Agency; Ministry of Health, Labour and Welfare; Takeda Science Foundation. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract By whole exome sequencing, we identified three de novo RHOBTB2 variants in three patients with epileptic encephalopathies (EEs). Interestingly, all three patients showed acute encephalopathy (febrile status epilepticus), with magnetic resonance imaging revealing hemisphere swelling or reduced diffusion in various brain regions. RHOBTB2 encodes Rho-related BTB domain-containing protein 2, an atypical Rho GTPase that is a substrate-specific adaptor or itself is a substrate for the Cullin-3 (CUL3)-based ubiquitin ligase complex. Transient expression experiments in Neuro-2a cells revealed that mutant RHOBTB2 was more abundant than wild-type RHOBTB2. Coexpression of CUL3 with RHOBTB2 decreased the level of wild-type RHOBTB2 but not the level of any of the three mutants, indicating impaired CUL3 complex-dependent degradation of the three mutants. These data indicate that RHOBTB2 variants are a rare genetic cause of EEs, in which acute encephalopathy might be a characteristic feature, and that precise regulation of RHOBTB2 levels is essential for normal brain function. Citing Literature Supporting Information Filename Description humu23550-sup-0001-SuppMat.pdf181.5 KB Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume39, Issue8August 2018Pages 1070-1075 RelatedInformation