Clinical and functional consequences of GRIA variants in patients with neurological diseases

Wenshu XiangWei; Riley E. Perszyk; Nana Liu; Yuchen Xu; Subhrajit Bhattacharya; Gil H. Shaulsky; Constance Smith-Hicks; Ali Fatemi; Andrew E. Fry; Kate Chandler; Tao Wang; Julie Vogt; Julie S. Cohen; Alex R. Paciorkowski; Annapurna Poduri; Yuehua Zhang; Shuang Wang; Yuping Wang; Qiongxiang Zhai; Fang Fang; Jie Leng; Kathryn Garber; Scott J. Myers; Robin Tobias Jauss; Kristen L. Park; Timothy A. Benke; Johannes R. Lemke; Hongjie Yuan; Yuwu Jiang; Stephen F. Traynelis

doi:10.1007/s00018-023-04991-6

Clinical and functional consequences of GRIA variants in patients with neurological diseases

Wenshu XiangWei, Riley E. Perszyk, Nana Liu, Yuchen Xu, Subhrajit Bhattacharya, Gil H. Shaulsky, Constance Smith-Hicks, Ali Fatemi, Andrew E. Fry, Kate Chandler, Tao Wang, Julie Vogt, Julie S. Cohen, Alex R. Paciorkowski, Annapurna Poduri, Yuehua Zhang, Shuang Wang, Yuping Wang, Qiongxiang Zhai, Fang FangJie Leng, Kathryn Garber, Scott J. Myers, Robin Tobias Jauss, Kristen L. Park, Timothy A. Benke, Johannes R. Lemke, Hongjie Yuan, Yuwu Jiang, Stephen F. Traynelis

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

Abstract

AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus, their functional characteristics are a critical determinant of brain function. We evaluate intolerance of each GRIA gene to genetic variation using 3DMTR and report here the functional consequences of 52 missense variants in GRIA1–4 identified in patients with various neurological disorders. These variants produce changes in agonist EC₅₀, response time course, desensitization, and/or receptor surface expression. We predict that these functional and localization changes will have important consequences for circuit function, and therefore likely contribute to the patients’ clinical phenotype. We evaluated the sensitivity of variant receptors to AMPAR-selective modulators including FDA-approved drugs to explore potential targeted therapeutic options.

Original language	English (US)
Article number	345
Journal	Cellular and Molecular Life Sciences
Volume	80
Issue number	11
DOIs	https://doi.org/10.1007/s00018-023-04991-6
State	Published - Nov 2023

Keywords

AMPA
Channelopathy
GRIA
GluA
Glutamate receptors
Translational study

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Pharmacology
Cellular and Molecular Neuroscience
Cell Biology

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10.1007/s00018-023-04991-6

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XiangWei, W., Perszyk, R. E., Liu, N., Xu, Y., Bhattacharya, S., Shaulsky, G. H., Smith-Hicks, C., Fatemi, A., Fry, A. E., Chandler, K., Wang, T., Vogt, J., Cohen, J. S., Paciorkowski, A. R., Poduri, A., Zhang, Y., Wang, S., Wang, Y., Zhai, Q., ... Traynelis, S. F. (2023). Clinical and functional consequences of GRIA variants in patients with neurological diseases. Cellular and Molecular Life Sciences, 80(11), Article 345. https://doi.org/10.1007/s00018-023-04991-6

XiangWei, W, Perszyk, RE, Liu, N, Xu, Y, Bhattacharya, S, Shaulsky, GH, Smith-Hicks, C , Fatemi, A, Fry, AE, Chandler, K, Wang, T, Vogt, J, Cohen, JS, Paciorkowski, AR, Poduri, A, Zhang, Y, Wang, S, Wang, Y, Zhai, Q, Fang, F, Leng, J, Garber, K, Myers, SJ, Jauss, RT, Park, KL, Benke, TA, Lemke, JR, Yuan, H, Jiang, Y & Traynelis, SF 2023, 'Clinical and functional consequences of GRIA variants in patients with neurological diseases', Cellular and Molecular Life Sciences, vol. 80, no. 11, 345. https://doi.org/10.1007/s00018-023-04991-6

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title = "Clinical and functional consequences of GRIA variants in patients with neurological diseases",

abstract = "AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus, their functional characteristics are a critical determinant of brain function. We evaluate intolerance of each GRIA gene to genetic variation using 3DMTR and report here the functional consequences of 52 missense variants in GRIA1–4 identified in patients with various neurological disorders. These variants produce changes in agonist EC50, response time course, desensitization, and/or receptor surface expression. We predict that these functional and localization changes will have important consequences for circuit function, and therefore likely contribute to the patients{\textquoteright} clinical phenotype. We evaluated the sensitivity of variant receptors to AMPAR-selective modulators including FDA-approved drugs to explore potential targeted therapeutic options.",

keywords = "AMPA, Channelopathy, GRIA, GluA, Glutamate receptors, Translational study",

author = "Wenshu XiangWei and Perszyk, {Riley E.} and Nana Liu and Yuchen Xu and Subhrajit Bhattacharya and Shaulsky, {Gil H.} and Constance Smith-Hicks and Ali Fatemi and Fry, {Andrew E.} and Kate Chandler and Tao Wang and Julie Vogt and Cohen, {Julie S.} and Paciorkowski, {Alex R.} and Annapurna Poduri and Yuehua Zhang and Shuang Wang and Yuping Wang and Qiongxiang Zhai and Fang Fang and Jie Leng and Kathryn Garber and Myers, {Scott J.} and Jauss, {Robin Tobias} and Park, {Kristen L.} and Benke, {Timothy A.} and Lemke, {Johannes R.} and Hongjie Yuan and Yuwu Jiang and Traynelis, {Stephen F.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.",

year = "2023",

month = nov,

doi = "10.1007/s00018-023-04991-6",

language = "English (US)",

volume = "80",

journal = "Cellular and Molecular Life Sciences",

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AU - XiangWei, Wenshu

AU - Perszyk, Riley E.

AU - Liu, Nana

AU - Xu, Yuchen

AU - Bhattacharya, Subhrajit

AU - Shaulsky, Gil H.

AU - Smith-Hicks, Constance

AU - Fatemi, Ali

AU - Fry, Andrew E.

AU - Chandler, Kate

AU - Wang, Tao

AU - Vogt, Julie

AU - Cohen, Julie S.

AU - Paciorkowski, Alex R.

AU - Poduri, Annapurna

AU - Zhang, Yuehua

AU - Wang, Shuang

AU - Wang, Yuping

AU - Zhai, Qiongxiang

AU - Fang, Fang

AU - Leng, Jie

AU - Garber, Kathryn

AU - Myers, Scott J.

AU - Jauss, Robin Tobias

AU - Park, Kristen L.

AU - Benke, Timothy A.

AU - Lemke, Johannes R.

AU - Yuan, Hongjie

AU - Jiang, Yuwu

AU - Traynelis, Stephen F.

PY - 2023/11

Y1 - 2023/11

N2 - AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus, their functional characteristics are a critical determinant of brain function. We evaluate intolerance of each GRIA gene to genetic variation using 3DMTR and report here the functional consequences of 52 missense variants in GRIA1–4 identified in patients with various neurological disorders. These variants produce changes in agonist EC50, response time course, desensitization, and/or receptor surface expression. We predict that these functional and localization changes will have important consequences for circuit function, and therefore likely contribute to the patients’ clinical phenotype. We evaluated the sensitivity of variant receptors to AMPAR-selective modulators including FDA-approved drugs to explore potential targeted therapeutic options.

AB - AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus, their functional characteristics are a critical determinant of brain function. We evaluate intolerance of each GRIA gene to genetic variation using 3DMTR and report here the functional consequences of 52 missense variants in GRIA1–4 identified in patients with various neurological disorders. These variants produce changes in agonist EC50, response time course, desensitization, and/or receptor surface expression. We predict that these functional and localization changes will have important consequences for circuit function, and therefore likely contribute to the patients’ clinical phenotype. We evaluated the sensitivity of variant receptors to AMPAR-selective modulators including FDA-approved drugs to explore potential targeted therapeutic options.

KW - AMPA

KW - Channelopathy

KW - GRIA

KW - GluA

KW - Glutamate receptors

KW - Translational study

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JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

IS - 11

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ER -

Clinical and functional consequences of GRIA variants in patients with neurological diseases

Abstract

Keywords

ASJC Scopus subject areas

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