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 Willaert; Christopher 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

doi:10.1002/ana.25032

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

Department of Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

58 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 language	English
Pages (from-to)	466-478
Number of pages	13
Journal	Annals of Neurology
Volume	82
Issue number	3
DOIs	https://doi.org/10.1002/ana.25032
Publication status	Published - 2017 Sept

Bibliographical note

Funding Information:
We thank the participating patients and their families. Yoonjin Kang and Young-Sook Kim assisted with the public data analysis. We thank the Yale Center for Mendelian Disorders (U54HG006504) for generating raw sequence data for a part of the recruited patients and their parents. We thank Janghoo Lim for critical reading of the manuscript. A part of the biospecimens and data used for this study was provided by the Biobank of Pusan National University Hospital, a member of the Korea Biobank Network. A part of this study was supported by the Post-genome Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (MSIP; NRF-2014M3C9A2064686; to M.C.), by the Basic Science Research Program through NRF funded by the Ministry of Education (NRF-2014R1A1A 2A16053266; to M.C.), by Brain Research Program (NRF-2015M3C7A1028396 to H.J.) and Bio & Medical Technology Development Program (NRF-2013M3A9D5072551 to H.J.) of NRF funded by MSIP by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI12C0066; to J.H.C), and under the framework of international cooperation program managed by NRF (NRF-2015K2A1A2070030; to H.J.C.).

Publisher Copyright:
© 2017 American Neurological Association

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/ana.25032

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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

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

@article{44a87f647d924d08bbfaaf359da78d02,

title = "GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy",

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.",

author = "Yongjin Yoo and Jane Jung and Lee, {Yoo Na} and Youngha Lee and Hyosuk Cho and Eunjung Na and Hong, {Jea Yeok} and Eunjin Kim and Lee, {Jin Sook} and Lee, {Je Sang} and Chansik Hong and Park, {Sang Yoon} and Jinhong Wie and Kathryn Miller and Natasha Shur and Cheryl Clow and Ebel, {Rose{\`a}nne S.} and DeBrosse, {Suzanne D.} and Henderson, {Lindsay B.} and Rebecca Willaert and Christopher Castaldi and Irina Tikhonova and Kaya Bilg{\"u}var and Shrikant Mane and Kim, {Ki Joong} and Hwang, {Yong Seung} and Lee, {Seok Geun} and Insuk So and Lim, {Byung Chan} and Choi, {Hee Jung} and Seong, {Jae Young} and Shin, {Yong Beom} and Hosung Jung and Chae, {Jong Hee} and Murim Choi",

note = "Funding Information: We thank the participating patients and their families. Yoonjin Kang and Young-Sook Kim assisted with the public data analysis. We thank the Yale Center for Mendelian Disorders (U54HG006504) for generating raw sequence data for a part of the recruited patients and their parents. We thank Janghoo Lim for critical reading of the manuscript. A part of the biospecimens and data used for this study was provided by the Biobank of Pusan National University Hospital, a member of the Korea Biobank Network. A part of this study was supported by the Post-genome Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (MSIP; NRF-2014M3C9A2064686; to M.C.), by the Basic Science Research Program through NRF funded by the Ministry of Education (NRF-2014R1A1A 2A16053266; to M.C.), by Brain Research Program (NRF-2015M3C7A1028396 to H.J.) and Bio & Medical Technology Development Program (NRF-2013M3A9D5072551 to H.J.) of NRF funded by MSIP by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI12C0066; to J.H.C), and under the framework of international cooperation program managed by NRF (NRF-2015K2A1A2070030; to H.J.C.). Publisher Copyright: {\textcopyright} 2017 American Neurological Association",

year = "2017",

month = sep,

doi = "10.1002/ana.25032",

language = "English",

volume = "82",

pages = "466--478",

journal = "Annals of Neurology",

issn = "0364-5134",

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TY - JOUR

T1 - GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy

AU - Yoo, Yongjin

AU - Jung, Jane

AU - Lee, Yoo Na

AU - Lee, Youngha

AU - Cho, Hyosuk

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.

AU - DeBrosse, Suzanne D.

AU - Henderson, Lindsay B.

AU - Willaert, Rebecca

AU - Castaldi, Christopher

AU - Tikhonova, Irina

AU - Bilgüvar, Kaya

AU - Mane, Shrikant

AU - Kim, Ki Joong

AU - Hwang, Yong Seung

AU - Lee, Seok Geun

AU - So, Insuk

AU - Lim, Byung Chan

AU - Choi, Hee Jung

AU - Seong, Jae Young

AU - Shin, Yong Beom

AU - Jung, Hosung

AU - Chae, Jong Hee

AU - Choi, Murim

N1 - Funding Information: We thank the participating patients and their families. Yoonjin Kang and Young-Sook Kim assisted with the public data analysis. We thank the Yale Center for Mendelian Disorders (U54HG006504) for generating raw sequence data for a part of the recruited patients and their parents. We thank Janghoo Lim for critical reading of the manuscript. A part of the biospecimens and data used for this study was provided by the Biobank of Pusan National University Hospital, a member of the Korea Biobank Network. A part of this study was supported by the Post-genome Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (MSIP; NRF-2014M3C9A2064686; to M.C.), by the Basic Science Research Program through NRF funded by the Ministry of Education (NRF-2014R1A1A 2A16053266; to M.C.), by Brain Research Program (NRF-2015M3C7A1028396 to H.J.) and Bio & Medical Technology Development Program (NRF-2013M3A9D5072551 to H.J.) of NRF funded by MSIP by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI12C0066; to J.H.C), and under the framework of international cooperation program managed by NRF (NRF-2015K2A1A2070030; to H.J.C.). Publisher Copyright: © 2017 American Neurological Association

PY - 2017/9

Y1 - 2017/9

N2 - 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.

AB - 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.

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JO - Annals of Neurology

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GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy

Abstract

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