儿童失神癫痫易感基因的研究进展_Journal of Epilepsy

Authors：

苏文婷 ^1,2 ,  牛争平 ²

1. ;
2. ;

Corresponding author：

牛争平, Email: nzp105@sina.com

Keywords：

儿童失神癫痫; 易感基因; 遗传

DOI：

10.7507/2096-0247.20170037

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癫痫为最常见神经系统疾病之一。据世界卫生组织(WHO)数据统计，世界癫痫患病率为4‰~10‰。研究表明，半数以上儿童癫痫的病因与遗传相关。只与遗传相关而无其他潜在病因的癫痫及癫痫综合征称之为遗传性癫痫，遗传性癫痫的主要类型是遗传性全面性癫痫，而儿童失神癫痫(Childhood absence epilepsy，CAE)属于遗传性全面性癫痫，约占儿童期起病癫痫的5%~15%。目前国内外虽已报道了一系列与癫痫相关的易感基因，并设计基因芯片作为基因筛查手段，但癫痫的发病原因及致病机制尚不明确。部分CAE患儿成年后出现肌阵挛发作、强直阵挛性发作等其他全面性发作类型，提示遗传性全面性癫痫可能有共同的易感基因。CAE具有典型的临床表型和脑电图特征，易于确保研究对象的一致性，对癫痫易感基因方面的研究有很大优势。总结CAE易感基因相关研究进展，对于阐明其发病机制、进一步了解CAE病因与发病机制，以及对遗传性癫痫的诊断、治疗、遗传咨询都具有重要意义。

Citation： 苏文婷, 牛争平. 儿童失神癫痫易感基因的研究进展. Journal of Epilepsy, 2017, 3(3): 238-242. doi: 10.7507/2096-0247.20170037 Copy

1.	Pal DK, Pong AW, Chung WK.Genetic evaluation and counseling for epilepsy.Nat Rev Neurol, 2010, 6(8):445-453.
2.	Scheffer IE.Genetic testing in epilepsy:what should you be doing.Epilepsy Curr, 2011, 11(4):107-111.
3.	Fong GC, Shah PU, Gee MN, et al. Childhood absence epilepsy with tonic-clonic seizures and electroencephalogram 3-4-Hz spike and multispike-slow wave complexes:linkage to chromosome 8q24.Am J Hum Genet, 1998, 63(4):1117-1129.
4.	Yalcn O.Genes and molecular mechanisms involved in the epileptogenesis of idiopathic absence epilepsies.Seizure, 2012, 21(2):79-86.
5.	Berkovic SF, Andermann F, Andermann E, et al. Concepts of absence epilepsies:discrete syndromes or biological continuum.Neurology, 1987, 37(6):993-1000.
6.	姜玉武, 谢涵.特发性全面性癫痫的遗传学研究进展.北京大学学报(医学版), 2013, 45(2):186-191.
7.	Chen Y, Lu J, Pan H, et al. Association between genetic variation of CACNA1H and childhood absence epilepsy.Ann Neurol, 2003, 54(2):239-243.
8.	吕建军, 张月华, 陈育才.T型钙通道基因CACNA1H是儿童失神癫的易感基因.中华儿科杂志, 2005, 43(2):131-136.
9.	Liang J, Zhang Y, Wang J, et al. New variants in the CACNA1H gene identified in childhood absence epilepsy.Neurosci Lett, 2006, 406(1-2):27-32.
10.	梁建明, 张月华, 吴希如.儿童失神癫痫易感基因的研究.中华医学遗传学杂志, 2006, 23 (3):298-302.
11.	Peloquin JB, Khosravani H, Barr W, et al. Functional analysis of Ca3.2 T-type calcium channel mutations linked to childhood absence epilepsy. Epilepsia, 2006, 47(3):655-658.
12.	Jouvenceau A, Eunson LH, Spauschus A, et al. Human epilepsy associated with dysfunction of the brain P/Q type calcium channel.Lancet, 2001, 358(9284):801-807.
13.	Imbrici P, Jaffe SL, Eunson LH, et al. Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain, 2004, 127(Pt12):2682-2692.
14.	Essay A, De Waard M, Lee DD, et al. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.Am J Hum Genet, 2000, 66(5):1531-1539.
15.	Everett KV, Chioza B, Aicardi J, et al. Linkage and association analysis of CACNG3 in childhood absence epilepsy.Eur J Hum Genet, 2007, 15(4):463-472.
16.	Haug K, Warnstedt M, Aleko AK, et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.Nature Genet, 2003, 33(4):527-532.
17.	Everett K, Chioza B, Aicardi J, et al. Linkage and mutational analysis of CLCN2 in childhood absence epilepsy.Epilepsy Res, 2007, 75(2-3):145-153.
18.	Stogmann E, Lichtner P, Baumgartner C, et al. Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.Neurogenetics, 2006, 7(4):265-268.
19.	Niemeyer MI, Cid LP, Sepulveda FV, et al. No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy.Nat Genet, 2010, 42(1):3.
20.	Maljevic S, Krampfl K, Cobilanschi J, et al. A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy.Ann Neurol, 2006, 59(6):983-987.
21.	Kang JQ, Shen W, Macdonald RL.Two molecular pathways (NMD and ERAD) contribute to a genetic epilepsy associated with the GABA (A) receptor GABRA1 PTC mutation, 975delC, S326fs328X. J Neurosci, 2009, 29(9):2833-2844.
22.	Dibbens LM, Harkin LA, Richards M, et al. The role of neuronal GABAA receptor subunit mutations in idiopathic generalized epilepsies.Neurosci Lett, 2009, 453(3):162-165.
23.	Hernandez CC, Gurba KN, Hu N, et al. The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6β22 and 6β2 GABA(A) receptor channel gating and expression.Physiol, 2011, 589(Pt 23):5857-5878.
24.	Feucht M, Fuchs K, Pichlbauer E, et al. Possible association between childhood absence epilepsy and the gene encoding GABRB3. Biol Psychiatry, 1999, 46(7):997-1002.
25.	Urak L, Feucht M, Fathi N, et al. A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity.Hum Molec Genet, 2006, 15(16):2533-2541.
26.	Tanaka M, Olsen RW, Medina MT, et al. Hyper glycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy.Am J Hum Genet, 2008, 82(6):1249-1261.
27.	Gurba KN, Hernandez CC, Hu N, et al. The GABRB3 mutation, G32R, associated with childhood absence epilepsy, alters α1βγ2L GABAA receptor expression and channel gating.J Biol Chem, 2012, 287(15):12083-12097.
28.	Wallace RH, Marini C, Petrou S, et a1. Mutant GABA(A) receptor gamma 2-subunit in childhood absence epilepsy and febrile seizures.Nat Genet, 2001, 28(1):49-52.
29.	Marini C, Harkin LA, Wallace RH, et al. Childhood absence epilepsy and febrile seizures:a family with a GABA(A) receptor mutation.Brain, 2003, 126(Pt 1):230-240.
30.	Tan HO, Reid CA, Single FN, et al.Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy.Proc Natl Acad Sci, 2007, 104(44):1536-17541.
31.	Goytain A, Hines RM, Quamme GA.Functional characterization of NIPA2, a selective Mg2+ transporter.Am J Physiol Cell Physiol, 2008, 295(4):944-953.
32.	Quamme GA.Molecular identification of ancient and modern mammalian magnesium transporters.Am J Physiol Cell Physiol, 2010, 298(3):407-429.
33.	张平平, 张月华, 桑田, 等.染色体15q11.2和15q13.3区域的微缺失与中国儿童失神癫痫的相关性.实用儿科临床杂志, 2012, 27(7):522-525.
34.	Jiang Y, Zhang Y, Zhang P, et al. NIPA2 located in 15q11.2 is mutated in patients with childhood absence epilepsy.Hum Genet, 2012, 131(7):1217-1224.
35.	Liu S, Shipley MT.Multiple conductances cooperatively regulate spontaneous bursting in mouse olfactory bulb external tufted cells.J Neurosci, 2008, 28(7):1625-1639.
36.	Mayer ML, Westbrook GL, Guthrie PB.Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones.Nature, 1984, 309(5965):261-263.
37.	Nowak L, Bregestovski P, Ascher P, et al. Magnesium gates glutamate-activated channels in mouse central neurones.Nature, 1984, 307(5950):462-465.
38.	Crest M, Gola M.Large conductance Ca(2+)-activated K+ channels are involved in both spike shaping and firing regulation in helix neurones.J Physiol, 1993, 465(7):265-287.
39.	Wenli G, Thomas S, Tim B, et al. Genotypic association of exonic LGI4 polymorphisms and childhood absence epilepsy.Neurogenetics, 2004, 5(1):41-44.
40.	Sugimoto Y, Morita R, Amano K, et al. Childhood absence epilepsy in 8q24:refinement of candidate region and construction of physical map.Genomics, 2000, 68(3):264-272.

1. Pal DK, Pong AW, Chung WK.Genetic evaluation and counseling for epilepsy.Nat Rev Neurol, 2010, 6(8):445-453.
2. Scheffer IE.Genetic testing in epilepsy:what should you be doing.Epilepsy Curr, 2011, 11(4):107-111.
3. Fong GC, Shah PU, Gee MN, et al. Childhood absence epilepsy with tonic-clonic seizures and electroencephalogram 3-4-Hz spike and multispike-slow wave complexes:linkage to chromosome 8q24.Am J Hum Genet, 1998, 63(4):1117-1129.
4. Yalcn O.Genes and molecular mechanisms involved in the epileptogenesis of idiopathic absence epilepsies.Seizure, 2012, 21(2):79-86.
5. Berkovic SF, Andermann F, Andermann E, et al. Concepts of absence epilepsies:discrete syndromes or biological continuum.Neurology, 1987, 37(6):993-1000.
6. 姜玉武, 谢涵.特发性全面性癫痫的遗传学研究进展.北京大学学报(医学版), 2013, 45(2):186-191.
7. Chen Y, Lu J, Pan H, et al. Association between genetic variation of CACNA1H and childhood absence epilepsy.Ann Neurol, 2003, 54(2):239-243.
8. 吕建军, 张月华, 陈育才.T型钙通道基因CACNA1H是儿童失神癫的易感基因.中华儿科杂志, 2005, 43(2):131-136.
9. Liang J, Zhang Y, Wang J, et al. New variants in the CACNA1H gene identified in childhood absence epilepsy.Neurosci Lett, 2006, 406(1-2):27-32.
10. 梁建明, 张月华, 吴希如.儿童失神癫痫易感基因的研究.中华医学遗传学杂志, 2006, 23 (3):298-302.
11. Peloquin JB, Khosravani H, Barr W, et al. Functional analysis of Ca3.2 T-type calcium channel mutations linked to childhood absence epilepsy. Epilepsia, 2006, 47(3):655-658.
12. Jouvenceau A, Eunson LH, Spauschus A, et al. Human epilepsy associated with dysfunction of the brain P/Q type calcium channel.Lancet, 2001, 358(9284):801-807.
13. Imbrici P, Jaffe SL, Eunson LH, et al. Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain, 2004, 127(Pt12):2682-2692.
14. Essay A, De Waard M, Lee DD, et al. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.Am J Hum Genet, 2000, 66(5):1531-1539.
15. Everett KV, Chioza B, Aicardi J, et al. Linkage and association analysis of CACNG3 in childhood absence epilepsy.Eur J Hum Genet, 2007, 15(4):463-472.
16. Haug K, Warnstedt M, Aleko AK, et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies.Nature Genet, 2003, 33(4):527-532.
17. Everett K, Chioza B, Aicardi J, et al. Linkage and mutational analysis of CLCN2 in childhood absence epilepsy.Epilepsy Res, 2007, 75(2-3):145-153.
18. Stogmann E, Lichtner P, Baumgartner C, et al. Mutations in the CLCN2 gene are a rare cause of idiopathic generalized epilepsy syndromes.Neurogenetics, 2006, 7(4):265-268.
19. Niemeyer MI, Cid LP, Sepulveda FV, et al. No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy.Nat Genet, 2010, 42(1):3.
20. Maljevic S, Krampfl K, Cobilanschi J, et al. A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy.Ann Neurol, 2006, 59(6):983-987.
21. Kang JQ, Shen W, Macdonald RL.Two molecular pathways (NMD and ERAD) contribute to a genetic epilepsy associated with the GABA (A) receptor GABRA1 PTC mutation, 975delC, S326fs328X. J Neurosci, 2009, 29(9):2833-2844.
22. Dibbens LM, Harkin LA, Richards M, et al. The role of neuronal GABAA receptor subunit mutations in idiopathic generalized epilepsies.Neurosci Lett, 2009, 453(3):162-165.
23. Hernandez CC, Gurba KN, Hu N, et al. The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6β22 and 6β2 GABA(A) receptor channel gating and expression.Physiol, 2011, 589(Pt 23):5857-5878.
24. Feucht M, Fuchs K, Pichlbauer E, et al. Possible association between childhood absence epilepsy and the gene encoding GABRB3. Biol Psychiatry, 1999, 46(7):997-1002.
25. Urak L, Feucht M, Fathi N, et al. A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity.Hum Molec Genet, 2006, 15(16):2533-2541.
26. Tanaka M, Olsen RW, Medina MT, et al. Hyper glycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy.Am J Hum Genet, 2008, 82(6):1249-1261.
27. Gurba KN, Hernandez CC, Hu N, et al. The GABRB3 mutation, G32R, associated with childhood absence epilepsy, alters α1βγ2L GABAA receptor expression and channel gating.J Biol Chem, 2012, 287(15):12083-12097.
28. Wallace RH, Marini C, Petrou S, et a1. Mutant GABA(A) receptor gamma 2-subunit in childhood absence epilepsy and febrile seizures.Nat Genet, 2001, 28(1):49-52.
29. Marini C, Harkin LA, Wallace RH, et al. Childhood absence epilepsy and febrile seizures:a family with a GABA(A) receptor mutation.Brain, 2003, 126(Pt 1):230-240.
30. Tan HO, Reid CA, Single FN, et al.Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy.Proc Natl Acad Sci, 2007, 104(44):1536-17541.
31. Goytain A, Hines RM, Quamme GA.Functional characterization of NIPA2, a selective Mg2+ transporter.Am J Physiol Cell Physiol, 2008, 295(4):944-953.
32. Quamme GA.Molecular identification of ancient and modern mammalian magnesium transporters.Am J Physiol Cell Physiol, 2010, 298(3):407-429.
33. 张平平, 张月华, 桑田, 等.染色体15q11.2和15q13.3区域的微缺失与中国儿童失神癫痫的相关性.实用儿科临床杂志, 2012, 27(7):522-525.
34. Jiang Y, Zhang Y, Zhang P, et al. NIPA2 located in 15q11.2 is mutated in patients with childhood absence epilepsy.Hum Genet, 2012, 131(7):1217-1224.
35. Liu S, Shipley MT.Multiple conductances cooperatively regulate spontaneous bursting in mouse olfactory bulb external tufted cells.J Neurosci, 2008, 28(7):1625-1639.
36. Mayer ML, Westbrook GL, Guthrie PB.Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones.Nature, 1984, 309(5965):261-263.
37. Nowak L, Bregestovski P, Ascher P, et al. Magnesium gates glutamate-activated channels in mouse central neurones.Nature, 1984, 307(5950):462-465.
38. Crest M, Gola M.Large conductance Ca(2+)-activated K+ channels are involved in both spike shaping and firing regulation in helix neurones.J Physiol, 1993, 465(7):265-287.
39. Wenli G, Thomas S, Tim B, et al. Genotypic association of exonic LGI4 polymorphisms and childhood absence epilepsy.Neurogenetics, 2004, 5(1):41-44.
40. Sugimoto Y, Morita R, Amano K, et al. Childhood absence epilepsy in 8q24:refinement of candidate region and construction of physical map.Genomics, 2000, 68(3):264-272.

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