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 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

doi:10.1016/j.isci.2020.101552

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

iScience. 2020 Sep 11;23(10):101552. doi: 10.1016/j.isci.2020.101552. eCollection 2020 Oct 23.

Authors

Weilai Dong^{1

2}, Sheng Chih Jin³, August Allocco⁴, Xue Zeng^{1

2}, Amar H Sheth⁴, Shreyas Panchagnula⁴, Annie Castonguay⁵, Louis-Étienne Lorenzo⁵, Barira Islam⁶, Geneviève Brindle⁵, Karine Bachand⁵, Jamie Hu⁴, Agata Sularz⁴, Jonathan Gaillard⁴, Jungmin Choi^{1

2

7}, Ashley Dunbar⁴, Carol Nelson-Williams¹, Emre Kiziltug⁴, Charuta Gavankar Furey⁴, Sierra Conine⁴, Phan Q Duy⁴, Adam J Kundishora⁴, Erin Loring¹, Boyang Li⁸, Qiongshi Lu⁹, Geyu Zhou¹⁰, Wei Liu¹⁰, Xinyue Li¹¹, Michael C Sierant^{1

2}, Shrikant Mane¹², Christopher Castaldi¹², Francesc López-Giráldez¹², James R Knight¹², Raymond F Sekula Jr¹³, J Marc Simard¹⁴, Emad N Eskandar¹⁵, Christopher Gottschalk¹⁶, Jennifer Moliterno⁴, Murat Günel⁴, Jason L Gerrard⁴, Sulayman Dib-Hajj^{17

18}, Stephen G Waxman^{17

18}, Fred G Barker 2nd^{19

20

21}, Seth L Alper²², Mohamed Chahine^{5

23}, Shozeb Haider⁶, Yves De Koninck^{5

24}, Richard P Lifton^{1

2}, Kristopher T Kahle^{4

25

26}

Affiliations

¹ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
² Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
³ Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
⁵ CERVO Brain Research Centre, Université Laval, Québec, QC, Canada.
⁶ University College London, School of Pharmacy, London, England.
⁷ Department of Biomedical Sciences, Korea University College of Medicine, 02841 Seoul, Korea.
⁸ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
⁹ Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.
¹⁰ Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
¹¹ School of Data Science, City University of Hong Kong, Hong Kong, China.
¹² Yale Center for Genome Analysis, West Haven, CT, USA.
¹³ Department of Neurological Surgery, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
¹⁴ Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁵ Department of Neurological Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, New York.
¹⁶ Headache Medicine, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
¹⁷ Center for Neuroscience & Regeneration Research, VA Connecticut Healthcare System, West Haven, CT, USA.
¹⁸ Department of Neurology; Yale University, New Haven, CT, USA.
¹⁹ Harvard Medical School, Boston, MA, USA.
²⁰ Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
²¹ Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
²² Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA, USA.
²³ Department of Medicine, Université Laval, Québec, QC, Canada.
²⁴ Department of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada.
²⁵ Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA.
²⁶ Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.

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.

Keywords: Genomics; Neuroscience; Structural Biology.

Abstract

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