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Understanding of novel genetic causes of Rett-like syndrome and the genetic relationship of Rett syndrome with epileptic encephalopathy : 레트-유사증후군의 새로운 유전인자 및 레트증후군와 간질뇌증의 유전적 관계에 대한 이해
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- Authors
- Advisor
- 최무림
- Major
- 의과대학 의과학과
- Issue Date
- 2018-08
- Publisher
- 서울대학교 대학원
- Description
- 학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의과학과, 2018. 8. 최무림.
- Abstract
- 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, I investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions.
I 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.
I 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.
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.
- Language
- English
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