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

Authors

• Weilai Dong, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
• Sheng Chih Jin, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
• August Allocco, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Xue Zeng, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
• Amar H. Sheth, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Shreyas Panchagnula, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Annie Castonguay, CERVO Brain Research Centre, Université Laval, Québec, QC, Canada.
• Louis-Étienne Lorenzo, CERVO Brain Research Centre, Université Laval, Québec, QC, Canada.
• Barira Islam, University College London, School of Pharmacy, London, England.
• Geneviève Brindle, CERVO Brain Research Centre, Université Laval, Québec, QC, Canada.
• Karine Bachand, CERVO Brain Research Centre, Université Laval, Québec, QC, Canada.
• Jamie Hu, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Agata Sularz, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Jonathan Gaillard, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Jungmin Choi, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
• Ashley Dunbar, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Carol Nelson-Williams, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
• Emre Kiziltug, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Charuta Gavankar Furey, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Sierra Conine, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Phan Q. Duy, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Adam J. Kundishora, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Erin Loring, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
• Boyang Li, Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
• Qiongshi Lu, Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.
• Geyu Zhou, Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
• Wei Liu, Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
• Xinyue Li, School of Data Science, City University of Hong Kong, Hong Kong, China.
• Michael C. Sierant, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
• Shrikant Mane, Yale Center for Genome Analysis, West Haven, CT, USA.
• Christopher Castaldi, Yale Center for Genome Analysis, West Haven, CT, USA.

Document Type

Article

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 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 Ca channel Ca3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

Publication Date

10-23-2020

Publication Title

iScience

E-ISSN

2589-0042

Volume

23

Issue

10

First Page

101552

PubMed ID

33083721

Digital Object Identifier (DOI)

10.1016/j.isci.2020.101552

Recommended Citation

Dong, Weilai; Jin, Sheng Chih; Allocco, August; Zeng, Xue; Sheth, Amar H.; Panchagnula, Shreyas; Castonguay, Annie; Lorenzo, Louis-Étienne; Islam, Barira; Brindle, Geneviève; Bachand, Karine; Hu, Jamie; Sularz, Agata; Gaillard, Jonathan; Choi, Jungmin; Dunbar, Ashley; Nelson-Williams, Carol; Kiziltug, Emre; Furey, Charuta Gavankar; Conine, Sierra; Duy, Phan Q.; Kundishora, Adam J.; Loring, Erin; Li, Boyang; Lu, Qiongshi; Zhou, Geyu; Liu, Wei; Li, Xinyue; Sierant, Michael C.; Mane, Shrikant; and Castaldi, Christopher, "Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia" (2020). Neurosurgery. 2402.
https://scholar.barrowneuro.org/neurosurgery/2402