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

Dong, Weilai; Jin, Sheng Chih; Allocco, August; Zeng, Xue; Sheth, Amar H.; Panchagnula, Shreyas; Castonguay, Annie; Lorenzo, Louis-Etienne; Islam, Barira; Brindle, Genevieve; 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; Castaldi, Christopher; Lopez-Giraldez, Francesc; Knight, James R.; Sekula, Raymond F., Jr.; Simard, J. Marc; Eskandar, Emad N.; Gottschalk, Christopher; Moliterno, Jennifer; Gunel, Murat; Gerrard, Jason L.; Dib-Hajj, Sulayman; Waxman, Stephen G.; Barker, Fred G., II; Alper, Seth L.; Chahine, Mohamed; Haider, Shozeb; De Koninck, Yves; Lifton, Richard P.; Kahle, Kristopher T.

doi:10.1016/j.isci.2020.101552

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

Dong, Weilai;
Jin, Sheng Chih;
Allocco, August;
Zeng, Xue;
Sheth, Amar H.;
... Choi, Jungmin;
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초록

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 gamma-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 alpha-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.

키워드

Genomics; Neuroscience; Structural Biology; FAMILIAL HEMIFACIAL SPASM; GENOME-WIDE ASSOCIATION; POSTERIOR CRANIAL FOSSA; DE-NOVO MUTATIONS; NEUROPATHIC PAIN; A RECEPTOR; NEUROVASCULAR RELATIONSHIPS; IMPULSE GENERATION; GENETIC-VARIATION; RAT MODEL

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

저자: Dong, Weilai; Jin, Sheng Chih; Allocco, August; Zeng, Xue; Sheth, Amar H.; Panchagnula, Shreyas; Castonguay, Annie; Lorenzo, Louis-Etienne; Islam, Barira; Brindle, Genevieve; 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; Castaldi, Christopher; Lopez-Giraldez, Francesc; Knight, James R.; Sekula, Raymond F., Jr.; Simard, J. Marc; Eskandar, Emad N.; Gottschalk, Christopher; Moliterno, Jennifer; Gunel, Murat; Gerrard, Jason L.; Dib-Hajj, Sulayman; Waxman, Stephen G.; Barker, Fred G., II; Alper, Seth L.; Chahine, Mohamed; Haider, Shozeb; De Koninck, Yves; Lifton, Richard P.; Kahle, Kristopher T.

DOI: 10.1016/j.isci.2020.101552

발행일: 2020-10-23

유형: Article

저널명: iScience

권: 23

호: 10