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

被引：29

作者：

Dong, Weilai ^{[1
,2
,7
]}

Jin, Sheng Chih ^{[3
]}

Allocco, August ^{[4
]}

Zeng, Xue ^{[1
,2
]}

Sheth, Amar H. ^{[4
]}

Panchagnula, Shreyas ^{[4
]}

Castonguay, Annie ^{[5
]}

Lorenzo, Louis-Etienne ^{[5
]}

Islam, Barira ^{[6
]}

Brindle, Genevieve ^{[5
]}

Bachand, Karine ^{[5
]}

Hu, Jamie ^{[4
]}

Sularz, Agata ^{[4
]}

Gaillard, Jonathan ^{[4
]}

Choi, Jungmin ^{[1
,2
,7
]}

Dunbar, Ashley ^{[4
]}

Nelson-Williams, Carol ^{[1
]}

Kiziltug, Emre ^{[4
]}

Furey, Charuta Gavankar ^{[4
]}

Conine, Sierra ^{[4
]}

Duy, Phan Q. ^{[4
]}

Kundishora, Adam J. ^{[4
]}

Loring, Erin ^{[1
]}

Li, Boyang ^{[8
]}

Lu, Qiongshi ^{[9
]}

Zhou, Geyu ^{[29
]}

Liu, Wei ^{[29
]}

Li, Xinyue ^{[28
]}

Sierant, Michael C. ^{[1
,2
]}

Mane, Shrikant ^{[10
]}

Castaldi, Christopher ^{[10
]}

Lopez-Giraldez, Francesc ^{[10
]}

Knight, James R. ^{[10
]}

Sekula, Raymond F., Jr. ^{[11
,12
]}

Simard, J. Marc ^{[13
]}

Eskandar, Emad N. ^{[14
]}

Gottschalk, Christopher ^{[15
]}

Moliterno, Jennifer ^{[4
]}

Gunel, Murat ^{[4
]}

Gerrard, Jason L. ^{[4
]}

Dib-Hajj, Sulayman ^{[16
,17
]}

Waxman, Stephen G. ^{[16
,17
]}

Barker, Fred G., II ^{[18
,19
,20
]}

Alper, Seth L. ^{[21
,22
,23
]}

Chahine, Mohamed ^{[5
,24
]}

Haider, Shozeb ^{[6
]}

De Koninck, Yves ^{[5
,25
]}

Lifton, Richard P. ^{[1
,2
]}

Kahle, Kristopher T. ^{[4
,26
,27
]}

机构：

[1] Yale Sch Med, Dept Genet, New Haven, CT USA

[2] Rockefeller Univ, Lab Human Genet & Genom, 1230 York Ave, New York, NY 10021 USA

[3] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[4] Yale Sch Med, Dept Neurosurg, New Haven, CT 06510 USA

[5] Univ Laval, CERVO Brain Res Ctr, Quebec City, PQ, Canada

[6] UCL, Sch Pharm, London, England

[7] Korea Univ, Dept Biomed Sci, Coll Med, Seoul 02841, South Korea

[8] Yale Sch Publ Hlth, Dept Biostat, New Haven, CT USA

[9] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI USA

[10] Yale Ctr Genome Anal, West Haven, CT USA

[11] Univ Pittsburgh, Sch Med, Dept Neurol Surg, Pittsburgh, PA 15261 USA

[12] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA

[13] Univ Maryland, Sch Med, Dept Neurosurg, Baltimore, MD 21201 USA

[14] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Neurol Surg, New York, NY USA

[15] Yale Sch Med, Dept Neurol, Headache Med, New Haven, CT USA

[16] VA Connecticut Healthcare Syst, Ctr Neurosci & Regenerat Res, West Haven, CT USA

[17] Yale Univ, Dept Neurol, New Haven, CT USA

[18] Harvard Med Sch, Boston, MA 02115 USA

[19] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA

[20] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA

[21] Beth Israel Deaconess Med Ctr, Div Nephrol, Boston, MA 02215 USA

[22] Beth Israel Deaconess Med Ctr, Ctr Vasc Biol, Boston, MA 02215 USA

[23] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[24] Univ Laval, Dept Med, Quebec City, PQ, Canada

[25] Univ Laval, Dept Psychiat & Neurosci, Quebec City, PQ, Canada

[26] Yale Sch Med, Dept Pediat, New Haven, CT 06510 USA

[27] Yale Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA

[28] City Univ Hong Kong, Sch Data Sci, Hong Kong, Peoples R China

[29] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT USA

来源：

ISCIENCE | 2020年 / 23卷 / 10期

关键词：

FAMILIAL HEMIFACIAL SPASM; GENOME-WIDE ASSOCIATION; POSTERIOR CRANIAL FOSSA; DE-NOVO MUTATIONS; NEUROPATHIC PAIN; A RECEPTOR; NEUROVASCULAR RELATIONSHIPS; IMPULSE GENERATION; GENETIC-VARIATION; RAT MODEL;

D O I：

10.1016/j.isci.2020.101552

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 gamma-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 alpha-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.

引用

页数：25

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