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

19 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

Fingerprint

Rett Syndrome
Brain Diseases
Phenotype
Mutation
Exome
Aminobutyrates
Xenopus
Animal Models
Cell Culture Techniques

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Yoo, Y., Jung, J., Lee, Y. N., Lee, Y., Cho, H., Na, E., ... 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

GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy. / Yoo, Yongjin; Jung, Jane; Lee, Yoo Na; Lee, Youngha; Cho, Hyosuk; Na, Eunjung; Hong, Jea Yeok; 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.

In: Annals of Neurology, Vol. 82, No. 3, 01.09.2017, p. 466-478.

Research output: Contribution to journalArticle

Yoo, Y, Jung, J, Lee, YN, Lee, Y, Cho, H, Na, E, Hong, JY, Kim, E, Lee, JS, Lee, JS, Hong, C, Park, SY, Wie, J, Miller, K, Shur, N, Clow, C, Ebel, RS, DeBrosse, SD, Henderson, LB, Willaert, R, Castaldi, C, Tikhonova, I, Bilgüvar, K, Mane, S, Kim, KJ, Hwang, YS, Lee, SG, So, I, Lim, BC, Choi, HJ, Seong, JY, Shin, YB, Jung, H, Chae, JH & Choi, M 2017, 'GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy', Annals of Neurology, vol. 82, no. 3, pp. 466-478. https://doi.org/10.1002/ana.25032
Yoo, Yongjin ; Jung, Jane ; Lee, Yoo Na ; Lee, Youngha ; Cho, Hyosuk ; Na, Eunjung ; Hong, Jea Yeok ; 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. / GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy. In: Annals of Neurology. 2017 ; Vol. 82, No. 3. pp. 466-478.
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AU - Lee, Yoo Na

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AU - Na, Eunjung

AU - Hong, Jea Yeok

AU - Kim, Eunjin

AU - Lee, Jin Sook

AU - Lee, Je Sang

AU - Hong, Chansik

AU - Park, Sang Yoon

AU - Wie, Jinhong

AU - Miller, Kathryn

AU - Shur, Natasha

AU - Clow, Cheryl

AU - Ebel, Roseànne S.

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AU - Henderson, Lindsay B.

AU - Willaert, Rebecca

AU - Castaldi, Christopher

AU - Tikhonova, Irina

AU - Bilgüvar, Kaya

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AU - Kim, Ki Joong

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AU - So, Insuk

AU - Lim, Byung Chan

AU - Choi, Hee Jung

AU - Seong, Jae Young

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