GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy

Yongjin Yoo, Jane Jung, Yoo Na Lee, Youngha Lee, Hyosuk Cho, Eunjung Na, Jea Yeok Hong, Eunjin Kim, Jin Sook Lee, Je Sang Lee, Chansik Hong, Sang Yoon Park, Jinhong Wie, Kathryn Miller, Natasha Shur, Cheryl Clow, Roseànne S. Ebel, Suzanne D. DeBrosse, Lindsay B. Henderson, Rebecca WillaertChristopher Castaldi, Irina Tikhonova, Kaya Bilgüvar, Shrikant Mane, Ki Joong Kim, Yong Seung Hwang, Seok Geun Lee, Insuk So, Byung Chan Lim, Hee Jung Choi, Jae Young Seong, Yong Beom Shin, Hosung Jung, Jong Hee Chae, Murim Choi

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466–478.

Original languageEnglish
Pages (from-to)466-478
Number of pages13
JournalAnnals of Neurology
Volume82
Issue number3
DOIs
Publication statusPublished - 2017 Sep 1

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Yoo, Y., Jung, J., Lee, Y. N., Lee, Y., Cho, H., Na, E., Hong, J. Y., Kim, E., Lee, J. S., Lee, J. S., Hong, C., Park, S. Y., Wie, J., Miller, K., Shur, N., Clow, C., Ebel, R. S., DeBrosse, S. D., Henderson, L. B., ... Choi, M. (2017). GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy. Annals of Neurology, 82(3), 466-478. https://doi.org/10.1002/ana.25032