{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:56:29Z","timestamp":1790610989544,"version":"4.1.0"},"reference-count":60,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,9,22]],"date-time":"2017-09-22T00:00:00Z","timestamp":1506038400000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003621","name":"Ministry of Science, ICT and Future Planning","doi-asserted-by":"publisher","award":["NRF\u20102014M3C9A2064686"],"award-info":[{"award-number":["NRF\u20102014M3C9A2064686"]}],"id":[{"id":"10.13039\/501100003621","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003766","name":"Ministry of Education","doi-asserted-by":"publisher","award":["NRF\u20102014R1A1A2A16053266"],"award-info":[{"award-number":["NRF\u20102014R1A1A2A16053266"]}],"id":[{"id":"10.13039\/501100003766","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003710","name":"KHIDI","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2017,9]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We screened novel genetic factors from 34 RTT\u2010like patients without <jats:italic>MECP2<\/jats:italic> mutations, which account for \u223c90% of RTT cases, by whole\u2010exome sequencing. The biological function of the discovered variants was assessed in cell culture and <jats:italic>Xenopus tropicalis<\/jats:italic> models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a recurring de novo variant in GABAB receptor R2 (<jats:italic>GABBR2<\/jats:italic>) that reduces the receptor function, whereas different <jats:italic>GABBR2<\/jats:italic> variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p><jats:italic>GABBR2<\/jats:italic> is a genetic factor that determines RTT\u2010 or EE\u2010like phenotype expression depending on the variant positions. <jats:italic>GABBR2<\/jats:italic>\u2010mediated \u03b3\u2010aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466\u2013478<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25032","type":"journal-article","created":{"date-parts":[[2017,8,31]],"date-time":"2017-08-31T10:03:31Z","timestamp":1504173811000},"page":"466-478","source":"Crossref","is-referenced-by-count":87,"title":["<i>GABBR2<\/i> mutations determine phenotype in rett syndrome and epileptic encephalopathy"],"prefix":"10.1002","volume":"82","author":[{"given":"Yongjin","family":"Yoo","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences Seoul National University College of Medicine Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoo\u2010Na","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine Korea University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngha","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Seoul National University College of Medicine Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyosuk","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Seoul National University College of Medicine Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunjung","family":"Na","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JeaYeok","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunjin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Sook","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Department of Genome Medicine and Science Gachon University Gil Medical Center Incheon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Je Sang","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine Pusan National University College of Medicine Pusan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chansik","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Physiology Chosun University School of Medicine Kwangju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang\u2010Yoon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Science in Korean Medicine, Cancer Preventive Material Developmental Research Center, College of Korean Medicine Kyung Hee University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhong","family":"Wie","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Seoul National University College of Medicine Seoul Republic of Korea"},{"name":"Department of Physiology Seoul National University College of Medicine Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Miller","sequence":"additional","affiliation":[{"name":"Albany Medical Center Albany NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Shur","sequence":"additional","affiliation":[{"name":"Albany Medical Center Albany NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl","family":"Clow","sequence":"additional","affiliation":[{"name":"Albany Medical Center Albany NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose\u00e0nne S.","family":"Ebel","sequence":"additional","affiliation":[{"name":"UH Cleveland Medical Center Center for Human Genetics Cleveland OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne D.","family":"DeBrosse","sequence":"additional","affiliation":[{"name":"UH Cleveland Medical Center Center for Human Genetics Cleveland OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay B.","family":"Henderson","sequence":"additional","affiliation":[{"name":"GeneDx 207 Perry Parkway Gaithersburg MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Willaert","sequence":"additional","affiliation":[{"name":"GeneDx 207 Perry Parkway Gaithersburg MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Castaldi","sequence":"additional","affiliation":[{"name":"Yale Center for Genome Analysis West Haven CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Tikhonova","sequence":"additional","affiliation":[{"name":"Yale Center for Genome Analysis West Haven CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaya","family":"Bilg\u00fcvar","sequence":"additional","affiliation":[{"name":"Yale Center for Genome Analysis West Haven CT"},{"name":"Department of Genetics Yale University School of Medicine New Haven CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrikant","family":"Mane","sequence":"additional","affiliation":[{"name":"Yale Center for Genome Analysis West Haven CT"},{"name":"Department of Genetics Yale University School of Medicine New Haven CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Joong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Seoul National University College of Medicine Seoul National University Children's Hospital Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Seung","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Seoul National University College of Medicine Seoul National University Children's Hospital Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0060-5777","authenticated-orcid":false,"given":"Seok\u2010Geun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Science in Korean Medicine, Cancer Preventive Material Developmental Research Center, College of Korean Medicine Kyung Hee University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Insuk","family":"So","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Seoul National University College of Medicine Seoul Republic of Korea"},{"name":"Department of Physiology Seoul National University College of Medicine Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung Chan","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Seoul National University College of Medicine Seoul National University Children's Hospital Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee\u2010Jung","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Seoul National University College of Natural Sciences Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Young","family":"Seong","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine Korea University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Beom","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine Pusan National University College of Medicine Pusan Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hosung","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science Yonsei University College of Medicine Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong\u2010Hee","family":"Chae","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Seoul National University College of Medicine Seoul National University Children's Hospital Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9195-1455","authenticated-orcid":false,"given":"Murim","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences Seoul National University College of Medicine Seoul Republic of Korea"},{"name":"Department of Pediatrics, Seoul National University College of Medicine Seoul National University Children's Hospital Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,9,22]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22124"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0387-7604(85)80048-6"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/13810"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2013-102113"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000291011.54508.aa"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/85899"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature16533"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0175-11.2012"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3077-12.2012"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09582"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.14199"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2011.12.010"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)00250-1"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.12652"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.08.013"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12439"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2012.03656.x"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073815601501"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10945"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14135"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.10.001"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1086\/375538"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.026237"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1086\/426460"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1086\/426462"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910672106"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12141"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-2106"},{"key":"e_1_2_8_30_1","first-page":"216","article-title":"Korean Variant Archive (KOVA): a reference database of genetic variations in the Korean population","volume":"7","author":"Lee S","year":"2017","journal-title":"Sci Rep"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.677"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2016.12.068"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphs.2016.10.002"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2015-103568"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22844"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/25360"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13396"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1249489"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.109.163220"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2007.06.003"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.16-05-01623.1996"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R112.386664"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2011.03.003"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80381-5"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(94)90155-4"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1997.69010365.x"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/363274a0"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.024463"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2777"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.012138"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4050-14.2015"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10989"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2016.01.007"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.2174\/138945012798868425"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3145-10.2010"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2015.66"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2760"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37132"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.42"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00323.x"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.07.014"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fana.25032","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.25032","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T11:05:03Z","timestamp":1696590303000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.25032"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9]]},"references-count":60,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2017,9]]}},"alternative-id":["10.1002\/ana.25032"],"URL":"https:\/\/doi.org\/10.1002\/ana.25032","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9]]}}}