iScience (Oct 2020)
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, II,
- Seth L. Alper,
- Mohamed Chahine,
- Shozeb Haider,
- Yves De Koninck,
- Richard P. Lifton,
- Kristopher T. Kahle
Affiliations
- Weilai Dong
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, 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; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, 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; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA; Department of Biomedical Sciences, Korea University College of Medicine, 02841 Seoul, Korea
- 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; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA
- Shrikant Mane
- Yale Center for Genome Analysis, West Haven, CT, USA
- Christopher Castaldi
- Yale Center for Genome Analysis, West Haven, CT, USA
- Francesc López-Giráldez
- Yale Center for Genome Analysis, West Haven, CT, USA
- James R. Knight
- Yale Center for Genome Analysis, West Haven, CT, USA
- Raymond F. Sekula, Jr.
- Department of Neurological Surgery, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- J. Marc Simard
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA
- Emad N. Eskandar
- Department of Neurological Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, New York
- Christopher Gottschalk
- Headache Medicine, Department of Neurology, Yale School of Medicine, New Haven, CT, USA
- Jennifer Moliterno
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
- Murat Günel
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
- Jason L. Gerrard
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA
- Sulayman Dib-Hajj
- Center for Neuroscience & Regeneration Research, VA Connecticut Healthcare System, West Haven, CT, USA; Department of Neurology; Yale University, New Haven, CT, USA
- Stephen G. Waxman
- Center for Neuroscience & Regeneration Research, VA Connecticut Healthcare System, West Haven, CT, USA; Department of Neurology; Yale University, New Haven, CT, USA
- Fred G. Barker, II
- Harvard Medical School, Boston, MA, USA; Cancer Center, Massachusetts General Hospital, Boston, MA, USA; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA
- Seth L. Alper
- Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA, USA
- Mohamed Chahine
- CERVO Brain Research Centre, Université Laval, Québec, QC, Canada; Department of Medicine, Université Laval, Québec, QC, Canada
- Shozeb Haider
- University College London, School of Pharmacy, London, England
- Yves De Koninck
- CERVO Brain Research Centre, Université Laval, Québec, QC, Canada; Department of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada
- Richard P. Lifton
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA
- Kristopher T. Kahle
- Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA; Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA; Corresponding author
- Journal volume & issue
-
Vol. 23,
no. 10
p. 101552
Abstract
Summary: 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.
