[P2-136~192] Poster Presentation 2

[P2-179] Severity of GABAB receptor R2 (GABBR2) mutations determines neurologic outcomes ranging from Rett-like phenotype to epileptic encephalopathy

^○Murim Choi^{1, 2} (1.Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea, 2.Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children’s Hospital, Seoul, Republic of Korea)

Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous clinical features often allocate patients in the boundary of the two conditions, complicating accurate diagnosis and proper medical interventions. Although previous studies revealed genetic causes that lead to the two diseases, specific molecular mechanism that allows understanding of the pathogenesis and relationship of the two conditions remains to be uncovered. Here we show GABAB receptor R2 (GABBR2) as a differentiating factor for RTT- or EE-like phenotype expression depending on the variant positions. By screening genetic factors from RTT-like patients without MECP2 mutations, which account for ~90% of RTT patients, we identified a recurring de novo variant in GABBR2 that reduces the receptor function, while different GABBR2 variants from EE patients possess more profound effect in reducing the receptor activity and more responsive to the agonist rescue in an animal model. Finally, transcriptome-wide analysis of developing human brain tissues demonstrated GABBR2 as a bridging factor that link between RTT- and EE-associated genes, further supporting the notion that GABBR2-mediated GABA signaling is a crucial factor in determining the severity and nature of the neurodevelopmental phenotypes.