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GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy.
Yoo, Yongjin; Jung, Jane; Lee, Yoo-Na; Lee, Youngha; Cho, Hyosuk; Na, Eunjung; Hong, JeaYeok; Kim, Eunjin; Lee, Jin Sook; Lee, Je Sang; Hong, Chansik; Park, Sang-Yoon; Wie, Jinhong; Miller, Kathryn; Shur, Natasha; Clow, Cheryl; Ebel, Roseànne S; DeBrosse, Suzanne D; Henderson, Lindsay B; Willaert, Rebecca; Castaldi, Christopher; Tikhonova, Irina; Bilgüvar, Kaya; Mane, Shrikant; Kim, Ki Joong; Hwang, Yong Seung; Lee, Seok-Geun; So, Insuk; Lim, Byung Chan; Choi, Hee-Jung; Seong, Jae Young; Shin, Yong Beom; Jung, Hosung; Chae, Jong-Hee; Choi, Murim.
Afiliación
  • Yoo Y; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Jung J; Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • Lee YN; Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
  • Lee Y; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Cho H; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Na E; Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • Hong J; Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • Kim E; Department of Anatomy, Brain Research Institute, and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • Lee JS; Department of Pediatrics, Department of Genome Medicine and Science, Gachon University Gil Medical Center, Incheon, Republic of Korea.
  • Lee JS; Department of Rehabilitation Medicine, Pusan National University College of Medicine, Pusan, Republic of Korea.
  • Hong C; Department of Physiology, Chosun University School of Medicine, Kwangju, Republic of Korea.
  • Park SY; Department of Science in Korean Medicine, Cancer Preventive Material Developmental Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
  • Wie J; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Miller K; Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Shur N; Albany Medical Center, Albany, NY.
  • Clow C; Albany Medical Center, Albany, NY.
  • Ebel RS; Albany Medical Center, Albany, NY.
  • DeBrosse SD; UH Cleveland Medical Center, Center for Human Genetics, Cleveland, OH.
  • Henderson LB; UH Cleveland Medical Center, Center for Human Genetics, Cleveland, OH.
  • Willaert R; GeneDx, 207 Perry Parkway, Gaithersburg, MD.
  • Castaldi C; GeneDx, 207 Perry Parkway, Gaithersburg, MD.
  • Tikhonova I; Yale Center for Genome Analysis, West Haven, CT.
  • Bilgüvar K; Yale Center for Genome Analysis, West Haven, CT.
  • Mane S; Yale Center for Genome Analysis, West Haven, CT.
  • Kim KJ; Department of Genetics, Yale University School of Medicine, New Haven, CT.
  • Hwang YS; Yale Center for Genome Analysis, West Haven, CT.
  • Lee SG; Department of Genetics, Yale University School of Medicine, New Haven, CT.
  • So I; Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea.
  • Lim BC; Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea.
  • Choi HJ; Department of Science in Korean Medicine, Cancer Preventive Material Developmental Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
  • Seong JY; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Shin YB; Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Jung H; Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea.
  • Chae JH; Department of Biological Sciences, Seoul National University College of Natural Sciences, Seoul, Republic of Korea.
  • Choi M; Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Ann Neurol ; 82(3): 466-478, 2017 Sep.
Article en En | MEDLINE | ID: mdl-28856709
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 γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466-478.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Espasmos Infantiles / Síndrome de Rett / Receptores de GABA-B / Mutación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Ann Neurol Año: 2017 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Espasmos Infantiles / Síndrome de Rett / Receptores de GABA-B / Mutación Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Ann Neurol Año: 2017 Tipo del documento: Article