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.
Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia
W. Dong,W. Dong,S. Jin,A. Allocco,Xue Zeng,Xue Zeng,A. Sheth,Shreyas Panchagnula,A. Castonguay,Louis-Etienne Lorenzo,Barira Islam,Geneviève Brindle,Karine Bachand,Jamie Hu,Agata K Sularz,Jonathan R Gaillard,Jungmin Choi,Jungmin Choi,Jungmin Choi,Ashley Dunbar,C. Nelson-Williams,E. Kiziltug,C. Furey,Sierra B Conine,P. Duy,Adam J. Kundishora,E. Loring,Boyang Li,Q. Lu,Geyu Zhou,Wei Liu,Xinyue Li,M. Sierant,M. Sierant,S. Mane,C. Castaldi,F. López-Giráldez,James R. Knight,R. Sekula,J. Simard,E. Eskandar,Christopher H Gottschalk,J. Moliterno,M. Gunel,J. Gerrard,S. Dib-Hajj,S. Waxman,F. Barker,S. Alper,M. Chahine,S. Haider,Y. Koninck,R. Lifton,R. Lifton,K. Kahle
Published 2020 in iScience
ABSTRACT
PUBLICATION RECORD
- Publication year
2020
- Venue
iScience
- Publication date
2020-09-11
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- cacna1h
The gene encoding the Cav3.2 T-type voltage-gated calcium channel alpha-1H subunit.
Aliases: Cav3.2, alpha-1H subunit
- face pain behavior
Behavioral evidence of facial pain measured in the mouse model.
Aliases: facial pain behavior
- gaba receptor-binding genes
Genes whose products participate in binding to GABA receptors or receptor complexes.
Aliases: GABA receptor binding genes
- gabrg1
The gene encoding the GABAA receptor gamma-1 subunit, a component of a ligand-gated chloride channel.
Aliases: GABAA receptor Cl- channel gamma-1 subunit, gamma-1 subunit
- multiplex kindreds
Families containing multiple members affected by trigeminal neuralgia and included in the sequencing cohort.
Aliases: multiplex families
- na+ and ca+ channels
Ion channels that conduct sodium or calcium ions across excitable cell membranes.
Aliases: sodium and calcium channels, voltage-gated Na+ and Ca+ channels
- parent-offspring trios
Family units consisting of an affected proband and both parents, used for trio-based analysis.
Aliases: trios
- rare damaging variants
Low-frequency genetic variants predicted to impair the function of their encoded proteins.
Aliases: rare deleterious variants, damaging variants
- trigeminal mechanical allodynia
Pain hypersensitivity in the trigeminal region elicited by normally non-painful mechanical stimulation.
Aliases: mechanical allodynia
- trigeminal neuralgia
A debilitating neuropathic face pain syndrome affecting the trigeminal nerve territory.
Aliases: TN
- whole exome sequencing
A sequencing approach that targets the protein-coding regions of the genome.
Aliases: WES, exome sequencing
REFERENCES
CITED BY
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