Investigation of IFIT3 and KCNS3 Gene Expression Patterns in the Peripheral Blood of Patients with Cryptogenic Epilepsy
Abstract
ABSTRACT
Objective: Epilepsy is a neurological disease characterized by recurrent seizures. Cryptogenic cases are those where there are no prior signs of brain damage and no clear etiology. The absence of an obvious causative pathology creates challenges in the clinical management of the disease. Gene expression studies aid in improved clinical care, in terms of providing a better sight into the etiology, or mechanisms of the disease. In this study, we examined the expression levels of IFIT3 and KCNS3 genes in peripheral bloods of cryptogenic epilepsy patients.
Methods: Our study included cryptogenic epilepsy patients (n=20) and healthy controls (n=20). The peripheral blood samples of participants were collected, and total RNAs were isolated. Obtained RNA samples were converted into complementary DNAs (cDNAs). Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) was conducted to measure relative expression levels of IFIT3 and KCNS3 genes. ACTB was assigned as the housekeeping gene.
Results: Accordingly, the expression levels of KCNS3 were higher in the patient group (p<0.0001), while IFIT3 levels did not show a statistically significant difference in patients compared to healthy controls.
Conclusion: These findings indicate that KCNS3, a potassium channel-related gene, may play a significant role in the pathogenesis of cryptogenic epilepsy. The lack of significant differences in IFIT3 expression further supports the hypothesis that channelopathy, rather than immune-related processes, is a more likely underlying mechanism in these patients.
Ethical Statement
This study was approved by the Bezmialem Vakif University Clinical Research Ethics Committee. (Project No: E.63008) Written informed consent was obtained from all subjects.
Supporting Institution
Bezmialem Vakif University
Project Number
20220601E
References
- Collaborators GBDE. Global, regional, and national burden of epilepsy, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. Apr 2019;18(4):357-375. doi:10.1016/S1474-4422(18)30454-X
- Thijs RD, Surges R, O'Brien TJ, Sander JW. Epilepsy in adults. Lancet. Feb 16 2019;393(10172):689-701. doi:10.1016/S0140-6736(18)32596-0
- Shorvon SD. The etiologic classification of epilepsy. Epilepsia. Jun 2011;52(6):1052-7. doi:10.1111/j.1528-1167.2011.03041.x
- Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. Apr 2017;58(4):512-521. doi:10.1111/epi.13709
- Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. Jul-Aug 1989;30(4):389-99. doi:10.1111/j.1528-1157.1989.tb05316.x
- Chow JSW, Poon TL. Emerging Trends in the Management of Cryptogenic Epilepsy. IntechOpen; 2022.
- Dwivedi R, Kaushik M, Tripathi M, Dada R, Tiwari P. Unraveling the genetic basis of epilepsy: Recent advances and implications for diagnosis and treatment. Brain Res. Nov 15 2024;1843:149120. doi:10.1016/j.brainres.2024.149120
- Yu Y, Sun FJ. Research progress on the role of inflammatory mediators in the pathogenesis of epilepsy. Ibrain. Spring 2025;11(1):44-58. doi:10.1002/ibra.12162
- Ng AC-H, Chahine M, Scantlebury MH, Appendino JP. Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights. Journal of Neurology. 2024;271(6):3063-3094.
- Stommel EW, Seguin R, Thadani VM, et al. Cryptogenic epilepsy: an infectious etiology? Epilepsia. 2001;42(3):436-438.
- Khan R, Chaturvedi P, Sahu P, et al. Role of potassium ion channels in epilepsy: Focus on current therapeutic strategies. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2024;23(1):67-87.
- Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. May 1 2001;29(9):e45. doi:10.1093/nar/29.9.e45
- Richens A. Clinical pharmacology and medical treatment. A textbook of epilepsy. 1993:524-527.
- Engel J, Pedley TA. Epilepsy: a comprehensive textbook. (No Title). 1998;
- Engel J, Jr. Report of the ILAE classification core group. Epilepsia. Sep 2006;47(9):1558-68. doi:10.1111/j.1528-1167.2006.00215.x
- Pitkanen A, Lukasiuk K. Molecular and cellular basis of epileptogenesis in symptomatic epilepsy. Epilepsy Behav. Jan 2009;14 Suppl 1:16-25. doi:10.1016/j.yebeh.2008.09.023
- Ellerkmann RK, Remy S, Chen J, et al. Molecular and functional changes in voltage-dependent Na(+) channels following pilocarpine-induced status epilepticus in rat dentate granule cells. Neuroscience. 2003;119(2):323-33. doi:10.1016/s0306-4522(03)00168-4
- Bezanilla F, Perozo E. The voltage sensor and the gate in ion channels. Adv Protein Chem. 2003;63:211-41. doi:10.1016/s0065-3233(03)63009-3
- Stafstrom CE. Pump-Opathies: Mutations in Na(+)-K(+)-ATPase Genes Produce Severe Developmental Epileptic Encephalopathies. Epilepsy Curr. Jan-Feb 2022;22(1):72-74. doi:10.1177/15357597211057356
- Brunklaus A, Ellis R, Stewart H, et al. Homozygous mutations in the SCN1A gene associated with genetic epilepsy with febrile seizures plus and Dravet syndrome in 2 families. Eur J Paediatr Neurol. Jul 2015;19(4):484-8. doi:10.1016/j.ejpn.2015.02.001
- Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol. Jun 1 2010;588(Pt 11):1849-59. doi:10.1113/jphysiol.2010.187484
- Grizel A, Glukhov G, Sokolova O. Mechanisms of activation of voltage-gated potassium channels. Acta Naturae (англоязычная версия). 2014;6(4 (23)):10-26.
- Köhling R, Wolfart J. Potassium channels in epilepsy. Cold Spring Harbor perspectives in medicine. 2016;6(5):a022871.
- Ohba C, Kato M, Takahashi N, et al. De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia. Sep 2015;56(9):e121-8. doi:10.1111/epi.13072
- Sands TT, Balestri M, Bellini G, et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia. Dec 2016;57(12):2019-2030. doi:10.1111/epi.13596
- Shepard AR, Rae JL. Electrically silent potassium channel subunits from human lens epithelium. Am J Physiol. Sep 1999;277(3):C412-24. doi:10.1152/ajpcell.1999.277.3.C412
- Barghaan J, Bahring R. Dynamic coupling of voltage sensor and gate involved in closed-state inactivation of kv4.2 channels. J Gen Physiol. Feb 2009;133(2):205-24. doi:10.1085/jgp.200810073
- Zhang W, Li Y, Xin S, et al. The emerging roles of IFIT3 in antiviral innate immunity and cellular biology. J Med Virol. Jan 2023;95(1):e28259. doi:10.1002/jmv.28259
- Xu S, Huang J, Xun Z, et al. IFIT3 Is Increased in Serum from Patients with Chronic Hepatitis B Virus (HBV) Infection and Promotes the Anti-HBV Effect of Interferon Alpha via JAK-STAT2 In Vitro. Microbiol Spectr. Dec 21 2022;10(6):e0155722. doi:10.1128/spectrum.01557-22
- Rawat C, Kushwaha S, Srivastava AK, Kukreti R. Peripheral blood gene expression signatures associated with epilepsy and its etiologic classification. Genomics. Jan 2020;112(1):218-224. doi:10.1016/j.ygeno.2019.01.017
- Wang J, Lin ZJ, Liu L, et al. Epilepsy-associated genes. Seizure. Jan 2017;44:11-20. doi:10.1016/j.seizure.2016.11.030
- Hsu MJ, Chang YC, Hsueh HM. Biomarker selection for medical diagnosis using the partial area under the ROC curve. BMC Res Notes. Jan 10 2014;7:25. doi:10.1186/1756-0500-7-25
Kriptojenik Epilepsi Hastalarının Periferik Kanında IFIT3 ve KCNS3 Gen Ekspresyon Paternlerinin İncelenmesi
Abstract
Amaç: Epilepsi, tekrarlayan nöbetlerle karakterize edilen bir nörolojik hastalıktır. Kriptojenik vakalar, beyin hasarına dair öncül belirtilerin olmadığı ve belirgin bir etiyolojinin tespit edilemediği durumları ifade eder. Belirgin bir nedensel patolojinin yokluğu, hastalığın klinik yönetiminde zorluklar oluşturmaktadır. Gen ekspresyon çalışmaları, hastalığın etiyolojisi veya mekanizmaları hakkında daha iyi bir bakış açısı sağlayarak klinik bakımın iyileştirilmesine katkıda bulunur. Bu çalışmada, kriptojenik epilepsi hastalarının periferik kanlarında IFIT3 ve KCNS3 genlerinin ekspresyon düzeyleri incelenmiştir.
Yöntem: Çalışmamızda kriptojenik epilepsi hastaları (n=20) ve sağlıklı kontrol grubu (n=20) yer aldı. Katılımcılardan periferik kan örnekleri alındı ve total RNA'lar izole edildi. Elde edilen RNA örnekleri, tamamlayıcı DNA'lara (cDNA) dönüştürüldü. IFIT3 ve KCNS3 genlerinin göreceli ekspresyon düzeylerini ölçmek için Gerçek Zamanlı Kantitatif Polimeraz Zincir Reaksiyonu (RT-qPCR) yapıldı. ACTB, referans gen olarak belirlendi.
Bulgular: KCNS3 gen ekspresyon düzeyleri hasta grubunda daha yüksek bulundu (p<0.0001), IFIT3 düzeyleri ise sağlıklı kontrollerle karşılaştırıldığında istatistiksel olarak anlamlı bir fark göstermedi.
Sonuç: Bu bulgular, potasyum kanalı ile ilişkili bir gen olan KCNS3'ün, kriptojenik epilepsinin patogenezinde önemli bir rol oynayabileceğini göstermektedir. IFIT3 ekspresyonunda anlamlı bir fark olmaması, bu hastalarda bağışıklıkla ilişkili süreçler yerine kanalopatinin daha olası bir mekanizma olduğunu desteklemektedir.
Project Number
20220601E
References
- Collaborators GBDE. Global, regional, and national burden of epilepsy, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. Apr 2019;18(4):357-375. doi:10.1016/S1474-4422(18)30454-X
- Thijs RD, Surges R, O'Brien TJ, Sander JW. Epilepsy in adults. Lancet. Feb 16 2019;393(10172):689-701. doi:10.1016/S0140-6736(18)32596-0
- Shorvon SD. The etiologic classification of epilepsy. Epilepsia. Jun 2011;52(6):1052-7. doi:10.1111/j.1528-1167.2011.03041.x
- Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. Apr 2017;58(4):512-521. doi:10.1111/epi.13709
- Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. Jul-Aug 1989;30(4):389-99. doi:10.1111/j.1528-1157.1989.tb05316.x
- Chow JSW, Poon TL. Emerging Trends in the Management of Cryptogenic Epilepsy. IntechOpen; 2022.
- Dwivedi R, Kaushik M, Tripathi M, Dada R, Tiwari P. Unraveling the genetic basis of epilepsy: Recent advances and implications for diagnosis and treatment. Brain Res. Nov 15 2024;1843:149120. doi:10.1016/j.brainres.2024.149120
- Yu Y, Sun FJ. Research progress on the role of inflammatory mediators in the pathogenesis of epilepsy. Ibrain. Spring 2025;11(1):44-58. doi:10.1002/ibra.12162
- Ng AC-H, Chahine M, Scantlebury MH, Appendino JP. Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights. Journal of Neurology. 2024;271(6):3063-3094.
- Stommel EW, Seguin R, Thadani VM, et al. Cryptogenic epilepsy: an infectious etiology? Epilepsia. 2001;42(3):436-438.
- Khan R, Chaturvedi P, Sahu P, et al. Role of potassium ion channels in epilepsy: Focus on current therapeutic strategies. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2024;23(1):67-87.
- Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. May 1 2001;29(9):e45. doi:10.1093/nar/29.9.e45
- Richens A. Clinical pharmacology and medical treatment. A textbook of epilepsy. 1993:524-527.
- Engel J, Pedley TA. Epilepsy: a comprehensive textbook. (No Title). 1998;
- Engel J, Jr. Report of the ILAE classification core group. Epilepsia. Sep 2006;47(9):1558-68. doi:10.1111/j.1528-1167.2006.00215.x
- Pitkanen A, Lukasiuk K. Molecular and cellular basis of epileptogenesis in symptomatic epilepsy. Epilepsy Behav. Jan 2009;14 Suppl 1:16-25. doi:10.1016/j.yebeh.2008.09.023
- Ellerkmann RK, Remy S, Chen J, et al. Molecular and functional changes in voltage-dependent Na(+) channels following pilocarpine-induced status epilepticus in rat dentate granule cells. Neuroscience. 2003;119(2):323-33. doi:10.1016/s0306-4522(03)00168-4
- Bezanilla F, Perozo E. The voltage sensor and the gate in ion channels. Adv Protein Chem. 2003;63:211-41. doi:10.1016/s0065-3233(03)63009-3
- Stafstrom CE. Pump-Opathies: Mutations in Na(+)-K(+)-ATPase Genes Produce Severe Developmental Epileptic Encephalopathies. Epilepsy Curr. Jan-Feb 2022;22(1):72-74. doi:10.1177/15357597211057356
- Brunklaus A, Ellis R, Stewart H, et al. Homozygous mutations in the SCN1A gene associated with genetic epilepsy with febrile seizures plus and Dravet syndrome in 2 families. Eur J Paediatr Neurol. Jul 2015;19(4):484-8. doi:10.1016/j.ejpn.2015.02.001
- Catterall WA, Kalume F, Oakley JC. NaV1.1 channels and epilepsy. J Physiol. Jun 1 2010;588(Pt 11):1849-59. doi:10.1113/jphysiol.2010.187484
- Grizel A, Glukhov G, Sokolova O. Mechanisms of activation of voltage-gated potassium channels. Acta Naturae (англоязычная версия). 2014;6(4 (23)):10-26.
- Köhling R, Wolfart J. Potassium channels in epilepsy. Cold Spring Harbor perspectives in medicine. 2016;6(5):a022871.
- Ohba C, Kato M, Takahashi N, et al. De novo KCNT1 mutations in early-onset epileptic encephalopathy. Epilepsia. Sep 2015;56(9):e121-8. doi:10.1111/epi.13072
- Sands TT, Balestri M, Bellini G, et al. Rapid and safe response to low-dose carbamazepine in neonatal epilepsy. Epilepsia. Dec 2016;57(12):2019-2030. doi:10.1111/epi.13596
- Shepard AR, Rae JL. Electrically silent potassium channel subunits from human lens epithelium. Am J Physiol. Sep 1999;277(3):C412-24. doi:10.1152/ajpcell.1999.277.3.C412
- Barghaan J, Bahring R. Dynamic coupling of voltage sensor and gate involved in closed-state inactivation of kv4.2 channels. J Gen Physiol. Feb 2009;133(2):205-24. doi:10.1085/jgp.200810073
- Zhang W, Li Y, Xin S, et al. The emerging roles of IFIT3 in antiviral innate immunity and cellular biology. J Med Virol. Jan 2023;95(1):e28259. doi:10.1002/jmv.28259
- Xu S, Huang J, Xun Z, et al. IFIT3 Is Increased in Serum from Patients with Chronic Hepatitis B Virus (HBV) Infection and Promotes the Anti-HBV Effect of Interferon Alpha via JAK-STAT2 In Vitro. Microbiol Spectr. Dec 21 2022;10(6):e0155722. doi:10.1128/spectrum.01557-22
- Rawat C, Kushwaha S, Srivastava AK, Kukreti R. Peripheral blood gene expression signatures associated with epilepsy and its etiologic classification. Genomics. Jan 2020;112(1):218-224. doi:10.1016/j.ygeno.2019.01.017
- Wang J, Lin ZJ, Liu L, et al. Epilepsy-associated genes. Seizure. Jan 2017;44:11-20. doi:10.1016/j.seizure.2016.11.030
- Hsu MJ, Chang YC, Hsueh HM. Biomarker selection for medical diagnosis using the partial area under the ROC curve. BMC Res Notes. Jan 10 2014;7:25. doi:10.1186/1756-0500-7-25
Details
| Primary Language | English |
|---|---|
| Subjects | Neurosciences (Other) |
| Journal Section | Research Articles |
| Authors | |
| Project Number | 20220601E |
| Publication Date | June 30, 2025 |
| Submission Date | January 16, 2025 |
| Acceptance Date | June 3, 2025 |
| Published in Issue | Year 2025 Volume: 8 Issue: 2 |
The articles in the Journal of "Acta Medica Nicomedia" are open access articles licensed under a Creative Commons Attribution-ShareAlike 4.0 International License at the web address https://dergipark.org.tr/tr/pub/actamednicomedia