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정제인 정호성(해부학교실) Ann Neurol
등록일 : 2017-09-05 오전 11:53:00       조회 : 151
첨   부 :
제1저자 유용진(서울대) 정제인(해부학교실, BK21)
교신저자 정호성(해부학교실, BK21) 채종희(서울대) 최무림(서울대)

Ann Neurol. 2017 Sep᝞(3):466-478. doi: 10.1002/ana.25032.
GABBR2 mutations determine phenotype in Rett syndrome and epileptic encephalopathy.
Yoo Y1, Jung J2, Lee YN3, Lee Y1, Cho H1, Na E2, Hong J2, Kim E2, Lee JS4, Lee JS5, Hong C6, Park SY7, Wie J1,8, Miller K9, Shur N9, Clow C9, Ebel RS10, DeBrosse SD10, Henderson LB11, Willaert R11, Castaldi C12, Tikhonova I12, Bilgü;var K12,13, Mane S12,13, Kim KJ14, Hwang YS14, Lee SG7, So I1,8, Lim BC14, Choi HJ15, Seong JY3, Shin YB5, Jung H2, Chae JH14, Choi M1,14.

Author information
1Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.2Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.3Graduate School of Medicine, Korea University, Seoul, 02841, Republic of Korea.4Department of Pediatrics, Department of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, 21936, Republic of Korea.5Department of Rehabilitation Medicine, Pusan National University College of Medicine, Pusan, 46241, Republic of Korea.6Department of Physiology, Chosun University School of Medicine, Kwangju, 61452, Republic of Korea.7Department of Science in Korean Medicine, Cancer Preventive Material Developmental Research Center, College of Korean Medicine, Kyung Hee University, Seoul, 02453, Republic of Korea.8Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.9Albany Medical Center, Albany, NY, 12208, USA.10UH Cleveland Medical Center, Center for Human Genetics, Cleveland, OH, 44106, USA.11GeneDx, 207 Perry Parkway, Gaithersburg, MD, 20877, USA.12Yale Center for Genome Analysis, West Haven, CT, 06516, USA.13Department of Genetics, Yale University School of Medicine, New Haven, CT, 06510, USA.14Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children''s Hospital, Seoul, 03080, Republic of Korea.15Department of Biological Sciences, Seoul National University College of Natural Sciences, Seoul, 08826, Republic of Korea.

Abstract
OBJECTIVE:
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.
METHODS:
We screened novel genetic factors from 34 RTT-like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models.
RESULTS:
We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model.
INTERPRETATION:
GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated GABA signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. This article is protected by copyright. All rights reserved.
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