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.

• Authors: 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 Jr, J Marc Simard, Emad N Eskandar, Christopher Gottschalk, Jennifer Moliterno, Murat Günel, Jason L Gerrard, Sulayman Dib-Hajj, Stephen G Waxman, Fred G Barker 2nd, Seth L Alper, Mohamed Chahine, Shozeb Haider, Yves De Koninck, Richard P Lifton, Kristopher T Kahle
• Journal: iScience (iScience) Vol. 23 Issue 10 Pg. 101552 (Oct 23 2020) ISSN: 2589-0042 [Electronic] United States
• PMID: 33083721 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors.