钙离子通道基因突变与癫痫_Journal of Epilepsy

Authors：

 陈璇 , 王罗俊 ,  邓艳春

第四军医大学西京医院神经内科（西安，710032）;

Corresponding author：

邓艳春, Email: yanchundeng@yahoo.com

Keywords：

癫痫; 钙离子通道; 基因

DOI：

10.7507/2096-0247.20160061

Video：

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引起癫痫发作的神经元阵发性同步异常放电与离子通道密切相关。因此，编码钙离子通道的基因成为癫痫病因的候选基因之一。现有的抗癫痫药物（AEDs）被证明其作用机制包括抑制钙通道活性。但目前还缺乏高选择性的钙离子通道阻断剂。了解不同发作类型的癫痫患者不同类型的钙离子通道编码基因突变，对理解癫痫的发病机制和今后的精准诊疗很有必要。现对钙离子通道及其分型、编码基因和已发现在癫痫患者中的突变作一综述。

Citation： 陈璇, 王罗俊, 邓艳春. 钙离子通道基因突变与癫痫. Journal of Epilepsy, 2016, 2(4): 344-348. doi: 10.7507/2096-0247.20160061 Copy

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2.	Traub RD. Neocortical pyramidal cells:a model with dendritic calcium conductance reproduces repetitive firing and epileptic behavior. Brain Res, 1979, 173(2):243-257.
3.	Diriong S, Lory P, Williams ME, et al. Chromosomal localization of the human genes for alpha-1A, alpha-1B, and alpha-1E 4. voltage-dependent Ca²⁺ channel subunits. Genomics, 1995, 30(12):605-609.
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5.	Jouveneeau A, Eunson LH, Spausehus A, et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel.Lancet, 2001, 358(9284):801-807.
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8.	Singh B, Monteil A, Bidaud I. Mutational analysis of CACNA1 Gin idiopathic generalized epilepsy. Hum mutant, 2007, 28(5):524-525.
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18.	Powers PA, SchererSW, Tsui LC, et al. Localization of the gene encoding the alpha-2/delta subunit (CACNL2A) of the human skeletal muscle voltage-dependent Ca²⁺ channel to chromosome 7q21-q22 by somatic cell hybrid analysis. Genomics, 1994, 19(7):192-193.
19.	Vergult S, Dheedene A, Meurs A, et al. Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability. Eur J Hum Genet, 2015, 23(5):628-632.
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21.	Kalsi G, Whiting P, Le Bourdelles. Localization of the human NMDAR2D receptor subunit gene (GRIN2D) to 19q13.1-qter, the NMDAR2A subunit gene to 16p13.2 (GRIN2A), and the NMDAR2C subunit gene (GRIN2C) to 17q24-q25 using somatic cell hybrid and radiation hybrid mapping panels. Genomics, 1998, 47(11):423-425.
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25.	Browne TR, Dreifuss FE, Dyken PR, et al. Ethosuximide in the treatment of absence (peptit mal) seizures. Neurology, 1975, 25(8):515-524.
26.	Kelly KM, Gross RA, Macdonal RL. Valproic acid selectively reduces the low-threshold (T) calcium current in rat nodose neurons. Neurosci Lett, 1990, 116(23):233-238.
27.	Biton V. Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol, 2007, 30(11):230-240.
28.	Lee CY, Chen CC, Liou HH. Levetiracetam inhibits glutamate transmission through presynaptic P/Q-type calcium channels on the granule cells of the dentate gyrus. Br J Pharmacol, 2009, 158(12):1753-1762.
29.	Hainsworth AH, McNaughton NC, Pereverzev A, et al. Actions of sipatrigine202W92 and lamotrigine on R-type and T-type Ca²⁺ channel currents. Eur J Pharmacol, 2003, 467(121):77-80.
30.	Rock DM, Kelly KM, Macdonald RL. Gabapentin actions on ligand-and voltage-gated responses in cultured rodent neurons. Epilepsy Res, 1993, 16(8):89-98.
31.	Liu L, Zheng T, Morris MJ, et al. The mechanism of carbamazepine aggravation of absence seizures. J Pharmacol Exp Ther, 2006, 319(23):790-798.
32.	Zhang X, Velumian AA, Jones OT. Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia, 2000, 41(Suppl 2):52-60.

1. Ertel EA. Nomenclature of voltage-gated calcium channels. Neuron, 2000, 25 (3):533-535.
2. Traub RD. Neocortical pyramidal cells:a model with dendritic calcium conductance reproduces repetitive firing and epileptic behavior. Brain Res, 1979, 173(2):243-257.
3. Diriong S, Lory P, Williams ME, et al. Chromosomal localization of the human genes for alpha-1A, alpha-1B, and alpha-1E 4. voltage-dependent Ca²⁺ channel subunits. Genomics, 1995, 30(12):605-609.
4. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca²⁺ channel gene CACNL1A4. Cell, 1996, 87(8):543-552.
5. Jouveneeau A, Eunson LH, Spausehus A, et al. Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel.Lancet, 2001, 358(9284):801-807.
6. Chioza B, Wilkie H, Nashef L. Association between the alpha-1A calcium channel gene CACNA1A and idiopathic generalized epilepsy. Neurology, 2001, 56(7):1245-1246.
7. Perez-Reyes E, Cribbs LL, Daud A, et al. Molecular characterization of a neuronal low-voltage-activated T-type calcium channel. Nature, 1998, 391(11):896-900.
8. Singh B, Monteil A, Bidaud I. Mutational analysis of CACNA1 Gin idiopathic generalized epilepsy. Hum mutant, 2007, 28(5):524-525.
9. Cribbs LL, Lee JH, Yang J, et al. Cloning and characterization of alpha-1H from human heart, a member of the T-type Ca²⁺ channel gene family. Circ Res, 1998, 83(6):103-109.
10. Chen Y, Lu J, Pan H, et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol, 2003, 54(7):239-243.
11. Heron SE, Phillips HA, Mulley JC, et al. Genetic variation of CACNA1H in idiopathic generalized epilepsy. Ann Neurol, 2004, 55(6):595-596.
12. Taviaux S, Williams ME, Harpold MM, et al. Assignment of human genes for beta-2 and beta-4 subunits of voltage-dependent Ca²⁺ channels to chromosomes 10p12 and 2q22-q23. Hum Genet, 1997, 100(2):151-154.
13. Escayg A, De Waard, Meisler MH. Coding and noncoding variation of the human calcium-channel beta(4)-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet, 2000, 66(7):1531-1539.
14. Black JL, Lennon VA. Identification and cloning of putative human neuronal voltage-gated calcium channel gamma-2 and gamma-3 subunits:neurologic implications. Mayo Clin Proc, 1999, 74(5):357-361.
15. Burgess DL, Davis CF, Gefrides LA. Identification of three novel Ca²⁺ channel gamma subunit genes reveals molecular diversification by tandem and chromosome duplication. Genome Res, 1999, 9(3):1204-1213.
16. Szepetowski P. Familial infantile convulsions and paroxysmal choreoathetosis:a new neurological syndrome linked to the pericentromeric region of human chromosome 16. Am J Hum Genet, 1997, 121(13):278-281.
17. Lee WL, Tay A, Ong HT, et al. Association of infantile convulsions with paroxysmal dyskinesias (ICCA syndrome):confirmation of linkage to human chromosome 16p12-q12 in a Chinese family. Hum Genet, 1998, 103(5):608-612.
18. Powers PA, SchererSW, Tsui LC, et al. Localization of the gene encoding the alpha-2/delta subunit (CACNL2A) of the human skeletal muscle voltage-dependent Ca²⁺ channel to chromosome 7q21-q22 by somatic cell hybrid analysis. Genomics, 1994, 19(7):192-193.
19. Vergult S, Dheedene A, Meurs A, et al. Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability. Eur J Hum Genet, 2015, 23(5):628-632.
20. Takano H, Onodera O, Tanaka H, et al. Chromosomal localization of the epsilon-1, epsilon-3, and zeta-1 subunit genes of the human NMDA receptor channel. Biochem Biophys Res Commun, 1993, 197(21):922-926.
21. Kalsi G, Whiting P, Le Bourdelles. Localization of the human NMDAR2D receptor subunit gene (GRIN2D) to 19q13.1-qter, the NMDAR2A subunit gene to 16p13.2 (GRIN2A), and the NMDAR2C subunit gene (GRIN2C) to 17q24-q25 using somatic cell hybrid and radiation hybrid mapping panels. Genomics, 1998, 47(11):423-425.
22. Endele S, Rosenberger G, Geider K, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nature Genet, 2010, 42(8):1021-1026.
23. Mandich P, Schito AM, Bellone E, et al. Mapping of the human NMDAR2B receptor subunit gene (GRIN2B) to chromosome 12p12. Genomics, 1994, 22(3):216-218.
24. Lemke JR, HendrickxR, Geider K, et al. GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Ann Neurol, 2014, 75(3):147-154.
25. Browne TR, Dreifuss FE, Dyken PR, et al. Ethosuximide in the treatment of absence (peptit mal) seizures. Neurology, 1975, 25(8):515-524.
26. Kelly KM, Gross RA, Macdonal RL. Valproic acid selectively reduces the low-threshold (T) calcium current in rat nodose neurons. Neurosci Lett, 1990, 116(23):233-238.
27. Biton V. Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol, 2007, 30(11):230-240.
28. Lee CY, Chen CC, Liou HH. Levetiracetam inhibits glutamate transmission through presynaptic P/Q-type calcium channels on the granule cells of the dentate gyrus. Br J Pharmacol, 2009, 158(12):1753-1762.
29. Hainsworth AH, McNaughton NC, Pereverzev A, et al. Actions of sipatrigine202W92 and lamotrigine on R-type and T-type Ca²⁺ channel currents. Eur J Pharmacol, 2003, 467(121):77-80.
30. Rock DM, Kelly KM, Macdonald RL. Gabapentin actions on ligand-and voltage-gated responses in cultured rodent neurons. Epilepsy Res, 1993, 16(8):89-98.
31. Liu L, Zheng T, Morris MJ, et al. The mechanism of carbamazepine aggravation of absence seizures. J Pharmacol Exp Ther, 2006, 319(23):790-798.
32. Zhang X, Velumian AA, Jones OT. Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia, 2000, 41(Suppl 2):52-60.

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