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Year 2021, Volume: 38 Issue: 3, 288 - 293, 01.05.2021

Abstract

References

  • Armijo, J.A., Shushtarian, M., Valdizan, E.M., et al. 2005. Ion channels and epilepsy. Curr Pharm Des.;11(15):1975-2003. doi:10.2174/1381612054021006
  • Bailey, J.N., Patterson, C., de Nijs, L., et al. 2017. EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality. Genet Med.;19(2):144-156. doi:10.1038/gim.2016.86
  • Bozzi, Y., Casarosa, S., Caleo, M., 2012. Epilepsy as a neurodevelopmental disorder. Front Psychiatry.;3:19. doi:10.3389/fpsyt.2012.00019
  • Chen, C.C., Lamping, K.G., Nuno, D.W., et al. 2003. Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels. Science.;302(5649):1416-1418. doi:10.1126/science.1089268
  • Chen, Y., Lu, J., Pan, H., et al. 2003. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol.;54(2):239-243. doi:10.1002/ana.10607
  • Chen, Z., Lusicic, A., O'Brien, T.J., et al. 2016. Psychotic disorders induced by antiepileptic drugs in people with epilepsy. Brain.;139(Pt 10):2668-2678. doi:10.1093/brain/aww196
  • Cheng, J., Randall, A., Baldi, P., 2006. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins. 1;62(4):1125-32.
  • de Nijs, L., Léon, C., Nguyen, L., et al. 2009. EFHC1 interacts with microtubules to regulate cell division and cortical development. Nat Neurosci.;12(10):1266-1274. doi:10.1038/nn.2390
  • Dibbens, L.M., Feng, H.J., Richards, M.C., et al. 2004. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet.;13(13):1315-1319. doi:10.1093/hmg/ddh146
  • Ding, L., Feng, H.J., Macdonald, R.L., et al. 2010. GABA(A) receptor alpha1 subunit mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy reduces the expression and alters the composition of wild type GABA(A) receptors. J Biol Chem.;285(34):26390-26405. doi:10.1074/jbc.M110.142299
  • Farrant, M., Nusser, Z., 2005. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci.;6(3):215-229. doi:10.1038/nrn1625
  • Feng, H.J., Kang, J.Q., Song, L., et al. 2006. Delta subunit susceptibility variants E177A and R220H associated with complex epilepsy alter channel gating and surface expression of alpha4beta2delta GABAA receptors. J Neurosci.;26(5):1499-1506. doi:10.1523/JNEUROSCI.2913-05.2006
  • Fisher, R.S., 2017. The new classification of seizures by the international league against epilepsy. Curr Neurol Neurosci Rep.;17: 48 DOI 10.1007/s11910-017-0758-6.
  • Gardiner, M., 2005. Genetics of idiopathic generalized epilepsies. Epilepsia.;46 Suppl 9:15-20. doi:10.1111/j.1528-1167.2005.00310.x
  • Grisar, T., Lakaye, B., de Nijs, L., et al. 2012. Myoclonin1/EFHC1 in cell division, neuroblast migration, synapse/dendrite formation in juvenile myoclonic epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds. Jasper's Basic Mechanisms of the Epilepsies. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US).
  • Helbig, I., Riggs, E.R., Barry, C.A., et al. 2018. The ClinGen Epilepsy Gene Curation Expert Panel-Bridging the divide between clinical domain knowledge and formal gene curation criteria. Hum Mutat.;39(11):1476-1484. doi:10.1002/humu.23632
  • Heron, S.E., Khosravani, H., Varela, D., et al. 2007a. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol.;62(6):560-568. doi:10.1002/ana.21169
  • Heron, S.E., Scheffer, I.E., Berkovic, S.F., et al. 2007b. Channelopathies in idiopathic epilepsy. Neurotherapeutics.;4(2):295-304. doi:10.1016/j.nurt.2007.01.009
  • Heyne, H.O., Singh, T., Stamberger, H., et al. 2018. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet.;50(7):1048-1053. doi:10.1038/s41588-018-0143-7
  • Imad, H., Zelano, J., Kumlien, E. 2015. Hypoglycemia and risk of seizures: a retrospective cross-sectional study. Seizure.;25:147-149. doi:10.1016/j.seizure.2014.10.005
  • Ishii, A., Kang, J.Q., Schornak, C.C., et al. 2017. A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. J Med Genet.;54(3):202-211. doi:10.1136/jmedgenet-2016-104083
  • Kahle, K.T., Merner, N.D., Friedel, P., et al. 2014. Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy. EMBO Rep.;15(7):766-774. doi:10.15252/embr.201438840
  • Kearney, J., Meisler, M., 2009. Single Gene Mutations in Inherited and Sporadic Epilepsy. In: Encyclopedia of Basic Epilepsy Research. Elsevier/Academic Press, London. 369-374
  • Khosravani, H., Altier, C., Simms, B., et al. 2004. Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J Biol Chem.;279(11):9681-9684. doi:10.1074/jbc.C400006200
  • Lachance-Touchette, P., Brown, P., Meloche, C., et al. 2011. Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy. Eur J Neurosci.;34(2):237-249. doi:10.1111/j.1460-9568.2011.07767.x
  • Lachance-Touchette, P., Choudhury, M., Stoica, A., et al. 2014. Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner. Front Cell Neurosci.;8:317. doi:10.3389/fncel.2014.00317
  • Merner, N.D., Chandler, M.R., Bourassa, C., et al. 2015. Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia. Front Cell Neurosci.;9:386. doi:10.3389/fncel.2015.00386
  • Niturad, C.E., Lev, D., Kalscheuer, V.M., et al. 2017. Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. Brain.;140(11):2879-2894. doi:10.1093/brain/awx236
  • Rajakulendran, S., Hanna, M.G., 2016. The Role of Calcium Channels in Epilepsy. Cold Spring Harb Perspect Med.;6(1):a022723. doi:10.1101/cshperspect.a022723
  • Rogers, M.F., Shihab, H.A., Mort, M., et al. 2018. FATHMM-XF: accurate prediction of pathogenic point mutations via extended features. Bioinformatics. 1;34(3):511-513. doi: 10.1093/bioinformatics/btx536.
  • Saint-Martin, C., Gauvain, G., Teodorescu, G., et al. 2009. Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy. Hum Mutat.;30(3):397-405. doi:10.1002/humu.20876
  • Saito, T., Ishii, A., Sugai, K., et al. 2017. A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures. Clin Genet.;92(6):654-658. doi:10.1111/cge.13049
  • Scheffer, I.E., Berkovic, S., Capovilla, G., et al. 2017. ILAE classification of the epilepsies: position paper of the ilae commission for classification and terminology. Epilepsia.;58(4):512-521. doi:10.1111/epi.13709
  • Stafstrom, C.E., Carmant, L., 2015. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med.;5(6):a022426. doi:10.1101/cshperspect.a022426
  • Stogmann, E., Lichtner, P., Baumgartner, C., et al. 2006. Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations. Neurology.;67(11):2029-2031. doi:10.1212/01.wnl.0000250254.67042.1b
  • Suzuki, T., Delgado-Escueta, A.V., Aguan, K., et al. 2004. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet.;36(8):842-849. doi:10.1038/ng1393
  • Venselaar, H., Te Beek, T.A., Kuipers, R.K., et al. 2010. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics. 8;11:548. doi: 10.1186/1471-2105-11-548.
  • Zoons, E., Weisfelt, M., de Gans, J., et al. 2008. Seizures in adults with bacterial meningitis. Neurology.;70(22 Pt 2):2109-2115. doi:10.1212/01.wnl.0000288178.91614.5d

Nonsynonymous variations of ion channel-related genes as risk factors in epilepsy

Year 2021, Volume: 38 Issue: 3, 288 - 293, 01.05.2021

Abstract

Recurrent seizures are characteristic to epilepsy, which often arise due to increased electrical activity. Ligand-gated ion channels are considered as key factors in epilepsy as they regulate and maintain neuronal membrane potential via regulating ion transportation. Therefore, this study aims to identify ion channel-related single nucleotide variations that are considered as risk factors in epilepsy and determine their potential effects on pathogenicity, protein stability and structure using in silico methods. For this purpose, ion channel-related mutations linked with epilepsy were retrieved from ClinVar. Pathogenicity scores and protein stability were predicted using FATHMM-XF and MUpro, respectively. Structural alterations were determined via HOPE server. We identified 17 epilepsy-related missense mutations, 11 of which were in ion channel-related genes. Nonsynonymous substitutions of p.E177A, p.D219N, p.A322D, p.R577Q, p.E282K, p.V831M and p.R1072C were determined as pathogenic, while all mutations resulted in varying degrees of decrease in overall protein stability. Furthermore, all variants were annotated with risk for disease and introduction of distinct side chains caused differences in size, charge and hydrophobicity, as well as contact with other proteins and ligands. In conclusion, mutations in ion channel-related genes were previously identified in several genetic association studies while their functional annotations were not addressed. The results of this study provide a functional explanation to the pathogenic effects of ion channel-related gene mutations that are considered as risk factors in epilepsy.

References

  • Armijo, J.A., Shushtarian, M., Valdizan, E.M., et al. 2005. Ion channels and epilepsy. Curr Pharm Des.;11(15):1975-2003. doi:10.2174/1381612054021006
  • Bailey, J.N., Patterson, C., de Nijs, L., et al. 2017. EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality. Genet Med.;19(2):144-156. doi:10.1038/gim.2016.86
  • Bozzi, Y., Casarosa, S., Caleo, M., 2012. Epilepsy as a neurodevelopmental disorder. Front Psychiatry.;3:19. doi:10.3389/fpsyt.2012.00019
  • Chen, C.C., Lamping, K.G., Nuno, D.W., et al. 2003. Abnormal coronary function in mice deficient in alpha1H T-type Ca2+ channels. Science.;302(5649):1416-1418. doi:10.1126/science.1089268
  • Chen, Y., Lu, J., Pan, H., et al. 2003. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol.;54(2):239-243. doi:10.1002/ana.10607
  • Chen, Z., Lusicic, A., O'Brien, T.J., et al. 2016. Psychotic disorders induced by antiepileptic drugs in people with epilepsy. Brain.;139(Pt 10):2668-2678. doi:10.1093/brain/aww196
  • Cheng, J., Randall, A., Baldi, P., 2006. Prediction of protein stability changes for single-site mutations using support vector machines. Proteins. 1;62(4):1125-32.
  • de Nijs, L., Léon, C., Nguyen, L., et al. 2009. EFHC1 interacts with microtubules to regulate cell division and cortical development. Nat Neurosci.;12(10):1266-1274. doi:10.1038/nn.2390
  • Dibbens, L.M., Feng, H.J., Richards, M.C., et al. 2004. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet.;13(13):1315-1319. doi:10.1093/hmg/ddh146
  • Ding, L., Feng, H.J., Macdonald, R.L., et al. 2010. GABA(A) receptor alpha1 subunit mutation A322D associated with autosomal dominant juvenile myoclonic epilepsy reduces the expression and alters the composition of wild type GABA(A) receptors. J Biol Chem.;285(34):26390-26405. doi:10.1074/jbc.M110.142299
  • Farrant, M., Nusser, Z., 2005. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci.;6(3):215-229. doi:10.1038/nrn1625
  • Feng, H.J., Kang, J.Q., Song, L., et al. 2006. Delta subunit susceptibility variants E177A and R220H associated with complex epilepsy alter channel gating and surface expression of alpha4beta2delta GABAA receptors. J Neurosci.;26(5):1499-1506. doi:10.1523/JNEUROSCI.2913-05.2006
  • Fisher, R.S., 2017. The new classification of seizures by the international league against epilepsy. Curr Neurol Neurosci Rep.;17: 48 DOI 10.1007/s11910-017-0758-6.
  • Gardiner, M., 2005. Genetics of idiopathic generalized epilepsies. Epilepsia.;46 Suppl 9:15-20. doi:10.1111/j.1528-1167.2005.00310.x
  • Grisar, T., Lakaye, B., de Nijs, L., et al. 2012. Myoclonin1/EFHC1 in cell division, neuroblast migration, synapse/dendrite formation in juvenile myoclonic epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds. Jasper's Basic Mechanisms of the Epilepsies. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US).
  • Helbig, I., Riggs, E.R., Barry, C.A., et al. 2018. The ClinGen Epilepsy Gene Curation Expert Panel-Bridging the divide between clinical domain knowledge and formal gene curation criteria. Hum Mutat.;39(11):1476-1484. doi:10.1002/humu.23632
  • Heron, S.E., Khosravani, H., Varela, D., et al. 2007a. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol.;62(6):560-568. doi:10.1002/ana.21169
  • Heron, S.E., Scheffer, I.E., Berkovic, S.F., et al. 2007b. Channelopathies in idiopathic epilepsy. Neurotherapeutics.;4(2):295-304. doi:10.1016/j.nurt.2007.01.009
  • Heyne, H.O., Singh, T., Stamberger, H., et al. 2018. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet.;50(7):1048-1053. doi:10.1038/s41588-018-0143-7
  • Imad, H., Zelano, J., Kumlien, E. 2015. Hypoglycemia and risk of seizures: a retrospective cross-sectional study. Seizure.;25:147-149. doi:10.1016/j.seizure.2014.10.005
  • Ishii, A., Kang, J.Q., Schornak, C.C., et al. 2017. A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. J Med Genet.;54(3):202-211. doi:10.1136/jmedgenet-2016-104083
  • Kahle, K.T., Merner, N.D., Friedel, P., et al. 2014. Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy. EMBO Rep.;15(7):766-774. doi:10.15252/embr.201438840
  • Kearney, J., Meisler, M., 2009. Single Gene Mutations in Inherited and Sporadic Epilepsy. In: Encyclopedia of Basic Epilepsy Research. Elsevier/Academic Press, London. 369-374
  • Khosravani, H., Altier, C., Simms, B., et al. 2004. Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J Biol Chem.;279(11):9681-9684. doi:10.1074/jbc.C400006200
  • Lachance-Touchette, P., Brown, P., Meloche, C., et al. 2011. Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy. Eur J Neurosci.;34(2):237-249. doi:10.1111/j.1460-9568.2011.07767.x
  • Lachance-Touchette, P., Choudhury, M., Stoica, A., et al. 2014. Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner. Front Cell Neurosci.;8:317. doi:10.3389/fncel.2014.00317
  • Merner, N.D., Chandler, M.R., Bourassa, C., et al. 2015. Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia. Front Cell Neurosci.;9:386. doi:10.3389/fncel.2015.00386
  • Niturad, C.E., Lev, D., Kalscheuer, V.M., et al. 2017. Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features. Brain.;140(11):2879-2894. doi:10.1093/brain/awx236
  • Rajakulendran, S., Hanna, M.G., 2016. The Role of Calcium Channels in Epilepsy. Cold Spring Harb Perspect Med.;6(1):a022723. doi:10.1101/cshperspect.a022723
  • Rogers, M.F., Shihab, H.A., Mort, M., et al. 2018. FATHMM-XF: accurate prediction of pathogenic point mutations via extended features. Bioinformatics. 1;34(3):511-513. doi: 10.1093/bioinformatics/btx536.
  • Saint-Martin, C., Gauvain, G., Teodorescu, G., et al. 2009. Two novel CLCN2 mutations accelerating chloride channel deactivation are associated with idiopathic generalized epilepsy. Hum Mutat.;30(3):397-405. doi:10.1002/humu.20876
  • Saito, T., Ishii, A., Sugai, K., et al. 2017. A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures. Clin Genet.;92(6):654-658. doi:10.1111/cge.13049
  • Scheffer, I.E., Berkovic, S., Capovilla, G., et al. 2017. ILAE classification of the epilepsies: position paper of the ilae commission for classification and terminology. Epilepsia.;58(4):512-521. doi:10.1111/epi.13709
  • Stafstrom, C.E., Carmant, L., 2015. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med.;5(6):a022426. doi:10.1101/cshperspect.a022426
  • Stogmann, E., Lichtner, P., Baumgartner, C., et al. 2006. Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations. Neurology.;67(11):2029-2031. doi:10.1212/01.wnl.0000250254.67042.1b
  • Suzuki, T., Delgado-Escueta, A.V., Aguan, K., et al. 2004. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet.;36(8):842-849. doi:10.1038/ng1393
  • Venselaar, H., Te Beek, T.A., Kuipers, R.K., et al. 2010. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics. 8;11:548. doi: 10.1186/1471-2105-11-548.
  • Zoons, E., Weisfelt, M., de Gans, J., et al. 2008. Seizures in adults with bacterial meningitis. Neurology.;70(22 Pt 2):2109-2115. doi:10.1212/01.wnl.0000288178.91614.5d
There are 38 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section Clinical Research
Authors

Burcu Biterge Süt 0000-0001-5756-5756

Hayriye Soytürk 0000-0002-0000-3768

Publication Date May 1, 2021
Submission Date December 24, 2020
Acceptance Date February 1, 2021
Published in Issue Year 2021 Volume: 38 Issue: 3

Cite

APA Biterge Süt, B., & Soytürk, H. (2021). Nonsynonymous variations of ion channel-related genes as risk factors in epilepsy. Journal of Experimental and Clinical Medicine, 38(3), 288-293.
AMA Biterge Süt B, Soytürk H. Nonsynonymous variations of ion channel-related genes as risk factors in epilepsy. J. Exp. Clin. Med. May 2021;38(3):288-293.
Chicago Biterge Süt, Burcu, and Hayriye Soytürk. “Nonsynonymous Variations of Ion Channel-Related Genes As Risk Factors in Epilepsy”. Journal of Experimental and Clinical Medicine 38, no. 3 (May 2021): 288-93.
EndNote Biterge Süt B, Soytürk H (May 1, 2021) Nonsynonymous variations of ion channel-related genes as risk factors in epilepsy. Journal of Experimental and Clinical Medicine 38 3 288–293.
IEEE B. Biterge Süt and H. Soytürk, “Nonsynonymous variations of ion channel-related genes as risk factors in epilepsy”, J. Exp. Clin. Med., vol. 38, no. 3, pp. 288–293, 2021.
ISNAD Biterge Süt, Burcu - Soytürk, Hayriye. “Nonsynonymous Variations of Ion Channel-Related Genes As Risk Factors in Epilepsy”. Journal of Experimental and Clinical Medicine 38/3 (May 2021), 288-293.
JAMA Biterge Süt B, Soytürk H. Nonsynonymous variations of ion channel-related genes as risk factors in epilepsy. J. Exp. Clin. Med. 2021;38:288–293.
MLA Biterge Süt, Burcu and Hayriye Soytürk. “Nonsynonymous Variations of Ion Channel-Related Genes As Risk Factors in Epilepsy”. Journal of Experimental and Clinical Medicine, vol. 38, no. 3, 2021, pp. 288-93.
Vancouver Biterge Süt B, Soytürk H. Nonsynonymous variations of ion channel-related genes as risk factors in epilepsy. J. Exp. Clin. Med. 2021;38(3):288-93.