Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia

Weilai Dong; Sheng Chih Jin; August Allocco; Xue Zeng; Amar H. Sheth; Shreyas Panchagnula; Annie Castonguay; Louis-Étienne Lorenzo; Barira Islam; Geneviève Brindle; Karine Bachand; Jamie Hu; Agata Sularz; Jonathan Gaillard; Jungmin Choi; Ashley Dunbar; Carol Nelson-Williams; Emre Kiziltug; Charuta Gavankar Furey; Sierra Conine; Phan Q. Duy; Adam J. Kundishora; Erin Loring; Boyang Li; Qiongshi Lu; Geyu Zhou; Wei Liu; Xinyue Li; Michael C. Sierant; Shrikant Mane; Christopher Castaldi; Francesc López-Giráldez; James R. Knight; Raymond F. Sekula; J. Marc Simard; Emad N. Eskandar; Christopher Gottschalk; Jennifer Moliterno; Murat Günel; Jason L. Gerrard; Sulayman Dib-Hajj; Stephen G. Waxman; Fred G. Barker; Seth L. Alper; Mohamed Chahine; Shozeb Haider; Yves De Koninck; Richard P. Lifton; Kristopher T. Kahle

doi:10.1016/j.isci.2020.101552

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia

Weilai Dong
, Sheng Chih Jin
, August Allocco
, Xue Zeng
, Amar H. Sheth
, Shreyas Panchagnula
, Annie Castonguay
, Louis-Étienne Lorenzo
, Barira Islam
, Geneviève Brindle
, Karine Bachand
, Jamie Hu
, Agata Sularz
, Jonathan Gaillard
, Jungmin Choi
, Ashley Dunbar
, Carol Nelson-Williams
, Emre Kiziltug
, Charuta Gavankar Furey
, Sierra Conine

Phan Q. Duy, Adam J. Kundishora, Erin Loring, Boyang Li, Qiongshi Lu, Geyu Zhou, Wei Liu, Xinyue Li, Michael C. Sierant, Shrikant Mane, Christopher Castaldi, Francesc López-Giráldez, James R. Knight, Raymond F. Sekula, J. Marc Simard, Emad N. Eskandar, Christopher Gottschalk, Jennifer Moliterno, Murat Günel, Jason L. Gerrard, Sulayman Dib-Hajj, Stephen G. Waxman, Fred G. Barker, Seth L. Alper, Mohamed Chahine, Shozeb Haider, Yves De Koninck, Richard P. Lifton, Kristopher T. Kahle^*

^*Corresponding author for this work

Department of Data Science

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

35 Citations (Scopus)

94 Downloads (CityUHK Scholars)

Abstract

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABA_A receptor Cl⁻ channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na⁺ and Ca⁺channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca²⁺channel Ca_v3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

Original language	English
Article number	101552
Journal	iScience
Volume	23
Issue number	10
Online published	11 Sept 2020
DOIs	https://doi.org/10.1016/j.isci.2020.101552
Publication status	Published - 23 Oct 2020

Research Keywords

Genomics
Neuroscience
Structural Biology

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This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

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10.1016/j.isci.2020.101552

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Dong, W., Jin, S. C., Allocco, A., Zeng, X., Sheth, A. H., Panchagnula, S., Castonguay, A., Lorenzo, L.-É., Islam, B., Brindle, G., Bachand, K., Hu, J., Sularz, A., Gaillard, J., Choi, J., Dunbar, A., Nelson-Williams, C., Kiziltug, E., Furey, C. G., ... Kahle, K. T. (2020). Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia. iScience, 23(10), Article 101552. https://doi.org/10.1016/j.isci.2020.101552

@article{58ffd9a324a64e6ea441f93f89f81ac9,

title = "Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia",

abstract = "Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl− channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.",

keywords = "Genomics, Neuroscience, Structural Biology, Genomics, Neuroscience, Structural Biology, Genomics, Neuroscience, Structural Biology",

author = "Weilai Dong and Jin, \{Sheng Chih\} and August Allocco and Xue Zeng and Sheth, \{Amar H.\} and Shreyas Panchagnula and Annie Castonguay and Louis-{\'E}tienne Lorenzo and Barira Islam and Genevi{\`e}ve Brindle and Karine Bachand and Jamie Hu and Agata Sularz and Jonathan Gaillard and Jungmin Choi and Ashley Dunbar and Carol Nelson-Williams and Emre Kiziltug and Furey, \{Charuta Gavankar\} and Sierra Conine and Duy, \{Phan Q.\} and Kundishora, \{Adam J.\} and Erin Loring and Boyang Li and Qiongshi Lu and Geyu Zhou and Wei Liu and Xinyue Li and Sierant, \{Michael C.\} and Shrikant Mane and Christopher Castaldi and Francesc L{\'o}pez-Gir{\'a}ldez and Knight, \{James R.\} and Sekula, \{Raymond F.\} and Simard, \{J. Marc\} and Eskandar, \{Emad N.\} and Christopher Gottschalk and Jennifer Moliterno and Murat G{\"u}nel and Gerrard, \{Jason L.\} and Sulayman Dib-Hajj and Waxman, \{Stephen G.\} and Barker, \{Fred G.\} and Alper, \{Seth L.\} and Mohamed Chahine and Shozeb Haider and \{De Koninck\}, Yves and Lifton, \{Richard P.\} and Kahle, \{Kristopher T.\}",

year = "2020",

month = oct,

day = "23",

doi = "10.1016/j.isci.2020.101552",

language = "English",

volume = "23",

number = "10",

}

Dong, W, Jin, SC, Allocco, A, Zeng, X, Sheth, AH, Panchagnula, S, Castonguay, A, Lorenzo, L-É, Islam, B, Brindle, G, Bachand, K, Hu, J, Sularz, A, Gaillard, J, Choi, J, Dunbar, A, Nelson-Williams, C, Kiziltug, E, Furey, CG, Conine, S, Duy, PQ, Kundishora, AJ, Loring, E, Li, B, Lu, Q, Zhou, G, Liu, W, Li, X, Sierant, MC, Mane, S, Castaldi, C, López-Giráldez, F, Knight, JR, Sekula, RF, Simard, JM, Eskandar, EN, Gottschalk, C, Moliterno, J, Günel, M, Gerrard, JL, Dib-Hajj, S, Waxman, SG, Barker, FG, Alper, SL, Chahine, M, Haider, S, De Koninck, Y, Lifton, RP & Kahle, KT 2020, 'Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia', iScience, vol. 23, no. 10, 101552. https://doi.org/10.1016/j.isci.2020.101552

TY - JOUR

T1 - Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia

AU - Dong, Weilai

AU - Jin, Sheng Chih

AU - Allocco, August

AU - Zeng, Xue

AU - Sheth, Amar H.

AU - Panchagnula, Shreyas

AU - Castonguay, Annie

AU - Lorenzo, Louis-Étienne

AU - Islam, Barira

AU - Brindle, Geneviève

AU - Bachand, Karine

AU - Hu, Jamie

AU - Sularz, Agata

AU - Gaillard, Jonathan

AU - Choi, Jungmin

AU - Dunbar, Ashley

AU - Nelson-Williams, Carol

AU - Kiziltug, Emre

AU - Furey, Charuta Gavankar

AU - Conine, Sierra

AU - Duy, Phan Q.

AU - Kundishora, Adam J.

AU - Loring, Erin

AU - Li, Boyang

AU - Lu, Qiongshi

AU - Zhou, Geyu

AU - Liu, Wei

AU - Li, Xinyue

AU - Sierant, Michael C.

AU - Mane, Shrikant

AU - Castaldi, Christopher

AU - López-Giráldez, Francesc

AU - Knight, James R.

AU - Sekula, Raymond F.

AU - Simard, J. Marc

AU - Eskandar, Emad N.

AU - Gottschalk, Christopher

AU - Moliterno, Jennifer

AU - Günel, Murat

AU - Gerrard, Jason L.

AU - Dib-Hajj, Sulayman

AU - Waxman, Stephen G.

AU - Barker, Fred G.

AU - Alper, Seth L.

AU - Chahine, Mohamed

AU - Haider, Shozeb

AU - De Koninck, Yves

AU - Lifton, Richard P.

AU - Kahle, Kristopher T.

PY - 2020/10/23

Y1 - 2020/10/23

N2 - Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl− channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

AB - Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl− channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

KW - Genomics

KW - Neuroscience

KW - Structural Biology

KW - Genomics

KW - Neuroscience

KW - Structural Biology

KW - Genomics

KW - Neuroscience

KW - Structural Biology

UR - https://www.scopus.com/pages/publications/85092127152

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85092127152&origin=recordpage

U2 - 10.1016/j.isci.2020.101552

DO - 10.1016/j.isci.2020.101552

M3 - RGC 21 - Publication in refereed journal

C2 - 33083721

SN - 2589-0042

VL - 23

JO - iScience

JF - iScience

IS - 10

M1 - 101552

ER -

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia

Abstract

Research Keywords

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