HCN single nucleotide polymorphism and genetic susceptibility of medial temporal lobe epilepsy_Journal of Epilepsy

Authors：

 QINJiaming ¹ , NIGuanzhong ¹ , CHENZiyi ¹ , FANGZiyan ² , CHENShuda ³ ,  CAIXiaodong ⁴

1. Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510000, China;
2. Guangzhou brain hospital, Guangzhou, 510000, China;
3. Guangzhou No. 1 People's Hospital, Guangzhou 510000, China;
4. Department of Neurology, Epilepsy Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510000, China;

Corresponding author：

CAIXiaodong, Email: lmzhou56@163.com

Keywords：

Medial temproal lobe epilespy; Single nucleotide polymorphism; Genetic susceptibility; HCN

DOI：

10.7507/2096-0247.20160057

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Objective Through Sequenom iPEX system analyzed the genetic susceptibility in patients with Medial temporal lobe epilepsy (MTLE) which screening hyperpolarization-activated cyclic nucleotide gated channel (HCN) subunit HCN1 and HCN2 single nucleotide polymorphism blood samples. Methods Patients with epilepsy who were diagnosed MTLE in our epileptic clinic from December 2013 to April 2016 were included in this study, total 143 cases. Healthy volunteers who received annual physical checkups were recruited to serve as controls total 120 cases. The group enter criterion according to a 2004 ILAE report mainly:①12~55 years old; ②attack forms:partial onset seizures or secondary tonic-closure-clonus attack, a common onset symptoms such as stomach gas rise feeling, sense of deja vu, automatism etc.; ③with or without febrile convulsions history; ④EEG displayed unilateral or bilateral temporal spike, sharp slow wave, or their spines slow-wave sample such as epilepsy wave; ⑤head MRI displayed hippocampal sclerosis. Exclusion criteria:①tumors; ②head MRI display focal cortical dysplasia (FCD). Using sequenom iPLEX technology platform to detect all the object of study of gene polymorphism sites total ten sites. All statistical tests were conducted using SPSS version 16.0. Results all sites fulfilled Hardy-Weinberg genetic balance. The results showed that HCN1 rs17344896 C/T, rs6451973 A/G and HCN2 rs12977194 A/G three polypeptide sites associated with MTLE, with statistical differences(P < 0.05). Conclusion HCN1 and HCN2 genetic suscepibility is one of possible mechanism of MTLE.

Citation： QINJiaming, NIGuanzhong, CHENZiyi, FANGZiyan, CHENShuda, CAIXiaodong. HCN single nucleotide polymorphism and genetic susceptibility of medial temporal lobe epilepsy. Journal of Epilepsy, 2016, 2(4): 322-328. doi: 10.7507/2096-0247.20160057 Copy

1.	Cendes F, Sakamoto AC, Spreafico R, et al. Epilepsies associated with hippocampal sclerosis. Acta Neuropathol, 2014, 128(1):21-37.
2.	Thom M. Hippocampal sclerosis in epilepsy:a neuropathology review. Neuropathol Appl Neurobiol, 2014, 40(5):520-543.
3.	Engel JJ, Bingaman W, Becker AJ. Advances in understanding the process of epileptogenesis based on patient. Epilepsia, 2003, 12(5):60-71.
4.	Steinlein OK, Noebels JL. Ion channels and epilepsy in man and mouse. Curr Opin Genet Dev, 2000, 10(3):286-291.
5.	Coan AC, Campos BM, Beltramini GC, et al. Distinct functional and structural MRI abnormalities in mesial temporal lobe epilepsy with and without hippocampal sclerosis. Epilepsia, 2014, 55(8):1187-1196.
6.	Scott RC. Consequences of febrile seizures in childhood. Curr Opin Pediatr, 2014, 26(6):662-667.
7.	Berkovic SF, Yasuda CL, Covolan RJ, et al. Familial temporal lobe epilepsy:a common disorder identified in twins. Ann Neurol, 1996, 40(2):227-235.
8.	Kobayashi E, Cendes F. Seizure outcome and hippocampal atrophy in familial mesial temporal lobe epilepsy. Neurology, 2001, 56(2):166-172.
9.	Santos NF, Sousa SC, Kobayashi E, et al. Clinical and genetic heterogeneity in familial temporal lobe epilepsy. Epilepsia, 2002, 43(Suppl 5):136.
10.	Kobayashi E, Torres FR, Sardinha JA, et al. Hippocampal atrophy and T2-weighted signal changes in familial mesial temporal lobe epilepsy. Neurology, 2003, 60(3):405-409.
11.	Pernhorst K, Cendes F, Lopes-Cendes I, et al. Rs6295 promoter variants of the serotonin type 1A receptor are differentially activated by c-Jun in vitro and correlate to transcript levels in human epileptic brain tissue. Brain Res, 2013, 1499(5):136-144.
12.	Lv RJ, He JS, Fu YH, et al. A polymorphism in CALHM1 is associated with temporal lobe epilepsy. Epilepsy Behav, 2011, 20(4):681-685.
13.	Balan S, Vellichirammal NN, Banerjee M, et al. Failure to find association between febrile seizures and SCN1A rs3812718 polymorphism in south Indian patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Epilepsy Res, 2012, 101(3):288-292.
14.	Buono RJ, Radhakrishnan K. Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility. Epilepsy Res, 2004, 58(2-3):175-183.
15.	Heuser K, Nagelhus EA, Taub? ll E, et al. Variants of the genes encoding AQP4 and Kir4.1 are associated with subgroups of patients with temporal lobe epilepsy. Epilepsy Res, 2010, 88(1):55-64.
16.	Manna I, Indahl U, Berg PR, et al. Failure to confirm association of a polymorphism in KCNMB4 gene with mesial temporal lobe epilepsy. Epilepsy Res, 2013, 106(1-2):284-287.
17.	Lv RJ, Shao XQ, Wu LW, et al. ASIC1a polymorphism is associated with temporal lobe epilepsy. Epilepsy Res, 2011, 96(1-2):74-80.
18.	Wang X, Lu Q, Jin LR, et al.Association between the gamma-aminobutyric acid type B receptor 1 and 2 gene polymorphisms and mesial temporal lobe epilepsy in a Han Chinese population. Epilepsy Res, 2008, 81(2-3):198-203.
19.	Manna I, Lien S, Nakken S, et al. A functional genetic variation of the 5-HTR2A receptor affects age at onset in patients with temporal lobe epilepsy. Ann Hum Genet, 2012, 76(4):277-282.
20.	Manna I, Gjerstad L, Ottersen OP, et al. No evidence for a role of the coding variant of the Toll-like receptor 4 gene in temporal lobe epilepsy. Seizure, 2013, 22(9):791-793.
21.	Kauffman MA, Levy EM, Consalvo D, et al. GABABR1 (G1465A) gene variation and temporal lobe epilepsy controversy:new evidence. Seizure, 2008, 17(6):567-571.
22.	Heuser K, Mordoh J, Kochen S, et al. Temporal lobe epilepsy and matrix metalloproteinase 9:a tempting relation but negative genetic association. Seizure, 2010, 19(6):335-338.
23.	Jamali S, Salzmann A, Perroud N, et al. Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures. PLOS One, 2010, 5(9):261-270.
24.	Balan S, Ponsole-Lenfant M, Cillario J, et al.GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures. Pharmacogenet Genomics, 2013, 23(11):605-610.
25.	Kauffman MA, Roll P, Roeckel-Trevisiol N, et al. Serotonin transporter gene variation and refractory mesial temporal epilepsy with hippocampal sclerosis. Epilepsy Res, 2009, 85(2-3):231-234.
26.	Santoro B, Tibbs GR. The HCN gene family:molecular basis of the hyperpolarization-activated pacemaker. Ann NY Acad Sci, 1999, 868(8):741-764.
27.	DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol, 1993, 55(10):455-472.
28.	Magee JC. Dendritic lh normalizes temporal summation in hippocampal CA1 neurons. Nat Neurosci, 1999, 2(6):508-514.
29.	Magee JC. Dendritic hyperpolarization-activated currents modify the integrative properties. J Neurosci, 1998, 18(19):7613-7624.
30.	Lupica CR, Bell JA, Hoffman AF. Contribution of the hyperpolarization-activated current (Ih) to membrane. J Neurophysiol, 2001, 86(1):261-268.
31.	Bender RA, Brewster A, Santoro B. Differential and age-dependent expression of hyperpolarization-activated cyclic. Neuroscience, 2001, 106(4):689-698.
32.	Santoro B, Chen S, Luthi A, et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker. J Neurosci, 2000, 20(14):5264-5275.
33.	Jung S, Pavlidis P, Shumyatsky GP, et al. Progressive dendritic HCN channelopathy during epileptogenesis in the rat pilocarpine model of epilepsy. J Neurosci, 2007, 27(47):13012-13021.
34.	Yun-Jung Oh, Jongju Na, Ji-Heon Jeong. Alterations in hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) expression in the hippocampus following pilocarpine-induced status epilepticus. BMB Reports, 2012, 45(11):635-640.
35.	Santoro B, Tibbs GR, Siegelbaum SA, et al. TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron, 2009, 62(6):802-813.
36.	Li X, Berkovic SF. No association between polymorphisms in the calcium homeostasis modulator 1 gene and mesial temporal lobe epilepsy risk in a Chinese population. Seizure, 2014, 23(3):231-233.
37.	Zhang S, P Kwan, L Baum. The potential role of CAMSAP1L1 in symptomatic epilepsy. Neurosci Lett, 2013, 556(11):146-151.
38.	Pernhorst K. Promoter variants determine gamma-aminobutyric acid homeostasis-related gene transcription in human epileptic hippocampi. J Neuropathol Exp Neurol, 2011, 70(12):1080-1088.
39.	Schenkel LC, Vears DF, Mulley JC, et al.Serotonin transporter gene (5HTT) polymorphisms and temporal lobe epilepsy. Epilepsy Res, 2011, 95(1-2):152-157.
40.	Stein JL, Pelekanos JT, McMahon JM, et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet, 2012, 44(5):552-561.
41.	Salzmann A, Malafosse A, Szepetowski P, et al. Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy. Hum Mutat, 2012, 33(1):124-135.
42.	Tan NC, Heron SE, Scheffer IE, et al. Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy. Neurology, 2004, 63(6):1090-1092.
43.	Kwan P, Zimprich A, Zimprich F, et al. Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A:correlation among phenotype, genotype, and mRNA expression. Pharmacogenet Genomics, 2008, 18(11):989-998.
44.	Escayg A, Pataraia E, Baumgartner C, et al. A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus——and prevalence of variants in patients with epilepsy. Am J Hum Genet, 2001, 68(4):866-873.
45.	Takahashi Y, Schlachter K, Gruber-Sedlmayr U, et al. Genetic variations of immunoregulatory genes associated with Rasmussen syndrome. Epilepsy Res, 2013, 107(3):238-243.
46.	McIntosh AM, Crespel A, Balzar J, et al. Genetic variation in Hyperpolarization-activated cyclic nucleotide-gated channels and its relationship with neuroticism, cognition and risk of depression. Front Genet, 2012, 3(1):116.

1. Cendes F, Sakamoto AC, Spreafico R, et al. Epilepsies associated with hippocampal sclerosis. Acta Neuropathol, 2014, 128(1):21-37.
2. Thom M. Hippocampal sclerosis in epilepsy:a neuropathology review. Neuropathol Appl Neurobiol, 2014, 40(5):520-543.
3. Engel JJ, Bingaman W, Becker AJ. Advances in understanding the process of epileptogenesis based on patient. Epilepsia, 2003, 12(5):60-71.
4. Steinlein OK, Noebels JL. Ion channels and epilepsy in man and mouse. Curr Opin Genet Dev, 2000, 10(3):286-291.
5. Coan AC, Campos BM, Beltramini GC, et al. Distinct functional and structural MRI abnormalities in mesial temporal lobe epilepsy with and without hippocampal sclerosis. Epilepsia, 2014, 55(8):1187-1196.
6. Scott RC. Consequences of febrile seizures in childhood. Curr Opin Pediatr, 2014, 26(6):662-667.
7. Berkovic SF, Yasuda CL, Covolan RJ, et al. Familial temporal lobe epilepsy:a common disorder identified in twins. Ann Neurol, 1996, 40(2):227-235.
8. Kobayashi E, Cendes F. Seizure outcome and hippocampal atrophy in familial mesial temporal lobe epilepsy. Neurology, 2001, 56(2):166-172.
9. Santos NF, Sousa SC, Kobayashi E, et al. Clinical and genetic heterogeneity in familial temporal lobe epilepsy. Epilepsia, 2002, 43(Suppl 5):136.
10. Kobayashi E, Torres FR, Sardinha JA, et al. Hippocampal atrophy and T2-weighted signal changes in familial mesial temporal lobe epilepsy. Neurology, 2003, 60(3):405-409.
11. Pernhorst K, Cendes F, Lopes-Cendes I, et al. Rs6295 promoter variants of the serotonin type 1A receptor are differentially activated by c-Jun in vitro and correlate to transcript levels in human epileptic brain tissue. Brain Res, 2013, 1499(5):136-144.
12. Lv RJ, He JS, Fu YH, et al. A polymorphism in CALHM1 is associated with temporal lobe epilepsy. Epilepsy Behav, 2011, 20(4):681-685.
13. Balan S, Vellichirammal NN, Banerjee M, et al. Failure to find association between febrile seizures and SCN1A rs3812718 polymorphism in south Indian patients with mesial temporal lobe epilepsy and hippocampal sclerosis. Epilepsy Res, 2012, 101(3):288-292.
14. Buono RJ, Radhakrishnan K. Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility. Epilepsy Res, 2004, 58(2-3):175-183.
15. Heuser K, Nagelhus EA, Taub? ll E, et al. Variants of the genes encoding AQP4 and Kir4.1 are associated with subgroups of patients with temporal lobe epilepsy. Epilepsy Res, 2010, 88(1):55-64.
16. Manna I, Indahl U, Berg PR, et al. Failure to confirm association of a polymorphism in KCNMB4 gene with mesial temporal lobe epilepsy. Epilepsy Res, 2013, 106(1-2):284-287.
17. Lv RJ, Shao XQ, Wu LW, et al. ASIC1a polymorphism is associated with temporal lobe epilepsy. Epilepsy Res, 2011, 96(1-2):74-80.
18. Wang X, Lu Q, Jin LR, et al.Association between the gamma-aminobutyric acid type B receptor 1 and 2 gene polymorphisms and mesial temporal lobe epilepsy in a Han Chinese population. Epilepsy Res, 2008, 81(2-3):198-203.
19. Manna I, Lien S, Nakken S, et al. A functional genetic variation of the 5-HTR2A receptor affects age at onset in patients with temporal lobe epilepsy. Ann Hum Genet, 2012, 76(4):277-282.
20. Manna I, Gjerstad L, Ottersen OP, et al. No evidence for a role of the coding variant of the Toll-like receptor 4 gene in temporal lobe epilepsy. Seizure, 2013, 22(9):791-793.
21. Kauffman MA, Levy EM, Consalvo D, et al. GABABR1 (G1465A) gene variation and temporal lobe epilepsy controversy:new evidence. Seizure, 2008, 17(6):567-571.
22. Heuser K, Mordoh J, Kochen S, et al. Temporal lobe epilepsy and matrix metalloproteinase 9:a tempting relation but negative genetic association. Seizure, 2010, 19(6):335-338.
23. Jamali S, Salzmann A, Perroud N, et al. Functional variant in complement C3 gene promoter and genetic susceptibility to temporal lobe epilepsy and febrile seizures. PLOS One, 2010, 5(9):261-270.
24. Balan S, Ponsole-Lenfant M, Cillario J, et al.GABRG2, rs211037 is associated with epilepsy susceptibility, but not with antiepileptic drug resistance and febrile seizures. Pharmacogenet Genomics, 2013, 23(11):605-610.
25. Kauffman MA, Roll P, Roeckel-Trevisiol N, et al. Serotonin transporter gene variation and refractory mesial temporal epilepsy with hippocampal sclerosis. Epilepsy Res, 2009, 85(2-3):231-234.
26. Santoro B, Tibbs GR. The HCN gene family:molecular basis of the hyperpolarization-activated pacemaker. Ann NY Acad Sci, 1999, 868(8):741-764.
27. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol, 1993, 55(10):455-472.
28. Magee JC. Dendritic lh normalizes temporal summation in hippocampal CA1 neurons. Nat Neurosci, 1999, 2(6):508-514.
29. Magee JC. Dendritic hyperpolarization-activated currents modify the integrative properties. J Neurosci, 1998, 18(19):7613-7624.
30. Lupica CR, Bell JA, Hoffman AF. Contribution of the hyperpolarization-activated current (Ih) to membrane. J Neurophysiol, 2001, 86(1):261-268.
31. Bender RA, Brewster A, Santoro B. Differential and age-dependent expression of hyperpolarization-activated cyclic. Neuroscience, 2001, 106(4):689-698.
32. Santoro B, Chen S, Luthi A, et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker. J Neurosci, 2000, 20(14):5264-5275.
33. Jung S, Pavlidis P, Shumyatsky GP, et al. Progressive dendritic HCN channelopathy during epileptogenesis in the rat pilocarpine model of epilepsy. J Neurosci, 2007, 27(47):13012-13021.
34. Yun-Jung Oh, Jongju Na, Ji-Heon Jeong. Alterations in hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) expression in the hippocampus following pilocarpine-induced status epilepticus. BMB Reports, 2012, 45(11):635-640.
35. Santoro B, Tibbs GR, Siegelbaum SA, et al. TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron, 2009, 62(6):802-813.
36. Li X, Berkovic SF. No association between polymorphisms in the calcium homeostasis modulator 1 gene and mesial temporal lobe epilepsy risk in a Chinese population. Seizure, 2014, 23(3):231-233.
37. Zhang S, P Kwan, L Baum. The potential role of CAMSAP1L1 in symptomatic epilepsy. Neurosci Lett, 2013, 556(11):146-151.
38. Pernhorst K. Promoter variants determine gamma-aminobutyric acid homeostasis-related gene transcription in human epileptic hippocampi. J Neuropathol Exp Neurol, 2011, 70(12):1080-1088.
39. Schenkel LC, Vears DF, Mulley JC, et al.Serotonin transporter gene (5HTT) polymorphisms and temporal lobe epilepsy. Epilepsy Res, 2011, 95(1-2):152-157.
40. Stein JL, Pelekanos JT, McMahon JM, et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet, 2012, 44(5):552-561.
41. Salzmann A, Malafosse A, Szepetowski P, et al. Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy. Hum Mutat, 2012, 33(1):124-135.
42. Tan NC, Heron SE, Scheffer IE, et al. Failure to confirm association of a polymorphism in ABCB1 with multidrug-resistant epilepsy. Neurology, 2004, 63(6):1090-1092.
43. Kwan P, Zimprich A, Zimprich F, et al. Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A:correlation among phenotype, genotype, and mRNA expression. Pharmacogenet Genomics, 2008, 18(11):989-998.
44. Escayg A, Pataraia E, Baumgartner C, et al. A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus——and prevalence of variants in patients with epilepsy. Am J Hum Genet, 2001, 68(4):866-873.
45. Takahashi Y, Schlachter K, Gruber-Sedlmayr U, et al. Genetic variations of immunoregulatory genes associated with Rasmussen syndrome. Epilepsy Res, 2013, 107(3):238-243.
46. McIntosh AM, Crespel A, Balzar J, et al. Genetic variation in Hyperpolarization-activated cyclic nucleotide-gated channels and its relationship with neuroticism, cognition and risk of depression. Front Genet, 2012, 3(1):116.

Journal of Epilepsy

HCN single nucleotide polymorphism and genetic susceptibility of medial temporal lobe epilepsy

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