CACNA1H基因变异与神经系统疾病_Journal of Epilepsy

Authors：

刘晓睿 ,  蒋莉

重庆医科大学附属儿童医院神经内科, 国家儿童健康与疾病临床医学研究中心, 儿童发育疾病研究教育部重点实验室, 儿科学重庆市重点实验室（重庆 400014）;

Corresponding author：

蒋莉, Email: dr_jiangcqmu@163.com

Keywords：

CACNA1H; T型钙通道; 癫痫; 孤独症谱系障碍; 肌萎缩侧索硬化

DOI：

10.7507/2096-0247.202111011

Video：

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T型钙离子通道是一种低电压依赖性介导钙离子跨膜转运的膜蛋白，由于其特殊的电生理特性，在调节神经元兴奋性中具有重要作用。目前研究发现CACNA1H突变所致T型钙离子通道异常与多种神经系统疾病发生密切相关，如特发性全面性癫痫，孤独症谱系疾病，肌萎缩侧索硬化等，虽然其作为易感基因在疾病发生发展中的作用已得到一定证实，但致病机制尚不明确，本综述针对T型钙通道在神经系统中的电生理学作用，及CACNA1H突变与部分神经系统疾病之间关系进行探讨，旨在为突变致病机制的研究提供思路，并为后续精准治疗提供依据。

Citation： 刘晓睿, 蒋莉. CACNA1H基因变异与神经系统疾病. Journal of Epilepsy, 2022, 8(2): 146-150. doi: 10.7507/2096-0247.202111011 Copy

1.	Fatt P, Katz B. The electrical properties of crustacean muscle fibres. J Physiol, 1953, 120(1-2): 171-204.
2.	Andrade A, Brennecke A, Mallat S, et al. Genetic associations between voltage-gated calcium channels and psychiatric disorders. Int J Mol Sci, 2019, 20(14): 3537.
3.	Ertel EA, Campbell KP, Harpold MM, et al. Nomenclature of voltage-gated calcium channels. Neuron, 2000, 25(3): 533-535.
4.	Lory P, Nicole S, Monteil A. Neuronal Cav3 channelopathies: recent progress and perspectives. Pflugers Arch, 2020, 472(7): 831-844.
5.	Weiss N, Zamponi GW. Genetic T-type calcium channelopathies. J Med Genet, 2020, 57(1): 1-10.
6.	Wolfe JT, Wang H, Howard J, et al. T-type calcium channel regulation by specific G-protein betagamma subunits. Nature, 2003, 424(6945): 209-213.
7.	Mochida S, Westenbroek RE, Yokoyama CT, et al. Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion neurons by expression of exogenous calcium channels. Proc Natl Acad Sci U S A, 2003, 100(5): 2813-2818.
8.	Perez-Reyes E, Lory P. Molecular biology of T-type calcium channels. CNS Neurol Disord Drug Targets, 2006, 5(6): 605-609.
9.	Williams ME, Washburn MS, Hans M, et al. Structure and functional characterization of a novel human low-voltage activated calcium channel. J Neurochem, 1999, 72(2): 791-799.
10.	Iftinca MC. Neuronal T-type calcium channels: what's new? Iftinca: T-type channel regulation. J Med Life, 2011, 4(2): 126-138.
11.	Deleuze C, David F, Béhuret S, et al. T-type calcium channels consolidate tonic action potential output of thalamic neurons to neocortex. J Neurosci, 2012, 32(35): 12228-12236.
12.	Cain SM, Tyson JR, Choi HB, et al. Ca(V) 3. 2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons. Epilepsia, 2018, 59(4): 778-791.
13.	Zamponi GW, Lory P, Perez-Reyes E. Role of voltage-gated calcium channels in epilepsy. Pflugers Arch, 2010, 460(2): 395-403.
14.	Coulon P, Herr D, Kanyshkova T, et al. Burst discharges in neurons of the thalamic reticular nucleus are shaped by calcium-induced calcium release. Cell Calcium, 2009, 46(5-6): 333-346.
15.	Tjaden J, Eickhoff A, Stahlke S, et al. Expression pattern of T-type Ca(2+) channels in cerebellar purkinje cells after VEGF treatment. Cells, 2021, 10(9): 2277.
16.	Cain SM, Snutch TP. Contributions of T-type calcium channel isoforms to neuronal firing. Channels (Austin), 2010, 4(6): 475-482.
17.	Su H, Sochivko D, Becker A, et al. Upregulation of a T-type Ca2+ channel causes a long-lasting modification of neuronal firing mode after status epilepticus. J Neurosci, 2002, 22(9): 3645-3655.
18.	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.
19.	Becker F, Reid CA, Hallmann K, et al. Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy. Epilepsia Open, 2017, 2(3): 334-342.
20.	Heron SE, Khosravani H, Varela D, et al. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol, 2007, 62(6): 560-568.
21.	Vitko I, Chen Y, Arias JM, et al. Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J Neurosci, 2005, 25(19): 4844-4855.
22.	Glauser TA, Holland K, O'brien VP, et al. Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy. Ann Neurol, 2017, 81(3): 444-453.
23.	Nigam A, Hargus NJ, Barker BS, et al. Inhibition of T-type calcium channels in mEC layer II stellate neurons reduces neuronal hyperexcitability associated with epilepsy. Epilepsy Res, 2019, 154: 132-138.
24.	Chourasia N, Ossó-Rivera H, Ghosh A, et al. Expanding the phenotypic spectrum of CACNA1H mutations. Pediatr Neurol, 2019, 93: 50-55.
25.	胡笑月华颖, 王艳萍. CACNA1H基因变异致癫痫伴肌阵挛-失张力发作1例临床及遗传学特征分析. 临床儿科杂志, 2020, 38(11): 821-823.
26.	Stringer RN, Jurkovicova-Tarabova B, Souza IA, et al. De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy. Mol Brain, 2021, 14(1): 126.
27.	Eckle VS, Shcheglovitov A, Vitko I, et al. Mechanisms by which a CACNA1H mutation in epilepsy patients increases seizure susceptibility. J Physiol, 2014, 592(4): 795-809.
28.	Zamponi GW. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat Rev Drug Discov, 2016, 15(1): 19-34.
29.	Zhong X, Liu JR, Kyle JW, et al. A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies. Hum Mol Genet, 2006, 15(9): 1497-1512.
30.	Becker AJ, Pitsch J, Sochivko D, et al. Transcriptional upregulation of Cav3. 2 mediates epileptogenesis in the pilocarpine model of epilepsy. J Neurosci, 2008, 28(49): 13341-13353.
31.	Proft J, Rzhepetskyy Y, Lazniewska J, et al. The CACNA1H mutation in the GAERS model of absence epilepsy enhances T-type Ca(2+) currents by altering calnexin-dependent trafficking of Ca(v)3. 2 channels. Sci Rep, 2017, 7(1): 11513.
32.	Kann O, Kovács R, Njunting M, et al. Metabolic dysfunction during neuronal activation in the ex vivo hippocampus from chronic epileptic rats and humans . Brain, 2005, 128(Pt 10): 2396-2407.
33.	Wang G, Bochorishvili G, Chen Y, et al. CaV3. 2 calcium channels control NMDA receptor-mediated transmission:a new mechanism for absence epilepsy. Genes Dev, 2015, 29(14): 1535-1551.
34.	De La Torre-Ubieta L, Won H, Stein JL, et al. Advancing the understanding of autism disease mechanisms through genetics. Nat Med, 2016, 22(4): 345-361.
35.	Liao X, Li Y. Genetic associations between voltage-gated calcium channels and autism spectrum disorder: a systematic review. Mol Brain, 2020, 13(1): 96.
36.	Huang IY, Hsu YL, Chen CC, et al. Excavatolide-B enhances contextual memory retrieval via repressing the delayed rectifier potassium current in the hippocampus. Mar Drugs, 2018, 16(11): 405.
37.	Splawski I, Yoo DS, Stotz SC, et al. CACNA1H mutations in autism spectrum disorders. J Biol Chem, 2006, 281(31): 22085-22091.
38.	Long S, Zhou H, Li S, et al. The clinical and genetic features of co-occurring epilepsy and autism spectrum disorder in Chinese children. Front Neurol, 2019, 10: 505.
39.	Rzhepetskyy Y, Lazniewska J, Blesneac I, et al. CACNA1H missense mutations associated with amyotrophic lateral sclerosis alter Cav3. 2 T-type calcium channel activity and reticular thalamic neuron firing. Channels (Austin), 2016, 10(6): 466-477.
40.	Steinberg KM, Yu B, Koboldt DC, et al. Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS. Sci Rep, 2015, 5: 9124.
41.	Stringer RN, Jurkovicova-Tarabova B, Huang S, et al. A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Ca(v)3. 2 T-type channel activity. Mol Brain, 2020, 13(1): 33.
42.	Sharma KR, Sheriff S, Maudsley A, et al. Diffusion tensor imaging of basal ganglia and thalamus in amyotrophic lateral sclerosis. J Neuroimaging, 2013, 23(3): 368-374.
43.	Park SB, Kiernan MC, Vucic S. Axonal excitability in amyotrophic lateral sclerosis: axonal excitability in ALS. Neurotherapeutics, 2017, 14(1): 78-90.
44.	Liu Z, Yuan Y, Wang M, et al. Mutation spectrum of amyotrophic lateral sclerosis in Central South China. Neurobiol Aging, 2021, 107: 181-188.
45.	Carter MT, Mcmillan HJ, Tomin A, et al. Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy. Channels (Austin), 2019, 13(1): 153-161.
46.	Souza IA, Gandini MA, Zamponi GW. Splice-variant specific effects of a CACNA1H mutation associated with writer's cramp. Mol Brain, 2021, 14(1): 145.
47.	Powell KL, Cain SM, Ng C, et al. A Cav3. 2 T-type calcium channel point mutation has splice-variant-specific effects on function and segregates with seizure expression in a polygenic rat model of absence epilepsy. J Neurosci, 2009, 29(2): 371-380.
48.	Calhoun JD, Huffman AM, Bellinski I, et al. CACNA1H variants are not a cause of monogenic epilepsy. Hum Mutat, 2020, 41(6): 1138-1144.
49.	Itcho K, Oki K, Ohno H, et al. Update on genetics of primary aldosteronism. Biomedicines, 2021, 9(4): 409.
50.	Falcón D, González MR, Sánchez DDPE, et al. Dexamethasone-induced upregulation of Ca(V)3. 2 T-type Ca(2+) channels in rat cardiac myocytes. J Steroid Biochem Mol Biol, 2018, 178: 193-202.

1. Fatt P, Katz B. The electrical properties of crustacean muscle fibres. J Physiol, 1953, 120(1-2): 171-204.
2. Andrade A, Brennecke A, Mallat S, et al. Genetic associations between voltage-gated calcium channels and psychiatric disorders. Int J Mol Sci, 2019, 20(14): 3537.
3. Ertel EA, Campbell KP, Harpold MM, et al. Nomenclature of voltage-gated calcium channels. Neuron, 2000, 25(3): 533-535.
4. Lory P, Nicole S, Monteil A. Neuronal Cav3 channelopathies: recent progress and perspectives. Pflugers Arch, 2020, 472(7): 831-844.
5. Weiss N, Zamponi GW. Genetic T-type calcium channelopathies. J Med Genet, 2020, 57(1): 1-10.
6. Wolfe JT, Wang H, Howard J, et al. T-type calcium channel regulation by specific G-protein betagamma subunits. Nature, 2003, 424(6945): 209-213.
7. Mochida S, Westenbroek RE, Yokoyama CT, et al. Subtype-selective reconstitution of synaptic transmission in sympathetic ganglion neurons by expression of exogenous calcium channels. Proc Natl Acad Sci U S A, 2003, 100(5): 2813-2818.
8. Perez-Reyes E, Lory P. Molecular biology of T-type calcium channels. CNS Neurol Disord Drug Targets, 2006, 5(6): 605-609.
9. Williams ME, Washburn MS, Hans M, et al. Structure and functional characterization of a novel human low-voltage activated calcium channel. J Neurochem, 1999, 72(2): 791-799.
10. Iftinca MC. Neuronal T-type calcium channels: what's new? Iftinca: T-type channel regulation. J Med Life, 2011, 4(2): 126-138.
11. Deleuze C, David F, Béhuret S, et al. T-type calcium channels consolidate tonic action potential output of thalamic neurons to neocortex. J Neurosci, 2012, 32(35): 12228-12236.
12. Cain SM, Tyson JR, Choi HB, et al. Ca(V) 3. 2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons. Epilepsia, 2018, 59(4): 778-791.
13. Zamponi GW, Lory P, Perez-Reyes E. Role of voltage-gated calcium channels in epilepsy. Pflugers Arch, 2010, 460(2): 395-403.
14. Coulon P, Herr D, Kanyshkova T, et al. Burst discharges in neurons of the thalamic reticular nucleus are shaped by calcium-induced calcium release. Cell Calcium, 2009, 46(5-6): 333-346.
15. Tjaden J, Eickhoff A, Stahlke S, et al. Expression pattern of T-type Ca(2+) channels in cerebellar purkinje cells after VEGF treatment. Cells, 2021, 10(9): 2277.
16. Cain SM, Snutch TP. Contributions of T-type calcium channel isoforms to neuronal firing. Channels (Austin), 2010, 4(6): 475-482.
17. Su H, Sochivko D, Becker A, et al. Upregulation of a T-type Ca2+ channel causes a long-lasting modification of neuronal firing mode after status epilepticus. J Neurosci, 2002, 22(9): 3645-3655.
18. 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.
19. Becker F, Reid CA, Hallmann K, et al. Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy. Epilepsia Open, 2017, 2(3): 334-342.
20. Heron SE, Khosravani H, Varela D, et al. Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol, 2007, 62(6): 560-568.
21. Vitko I, Chen Y, Arias JM, et al. Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J Neurosci, 2005, 25(19): 4844-4855.
22. Glauser TA, Holland K, O'brien VP, et al. Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy. Ann Neurol, 2017, 81(3): 444-453.
23. Nigam A, Hargus NJ, Barker BS, et al. Inhibition of T-type calcium channels in mEC layer II stellate neurons reduces neuronal hyperexcitability associated with epilepsy. Epilepsy Res, 2019, 154: 132-138.
24. Chourasia N, Ossó-Rivera H, Ghosh A, et al. Expanding the phenotypic spectrum of CACNA1H mutations. Pediatr Neurol, 2019, 93: 50-55.
25. 胡笑月华颖, 王艳萍. CACNA1H基因变异致癫痫伴肌阵挛-失张力发作1例临床及遗传学特征分析. 临床儿科杂志, 2020, 38(11): 821-823.
26. Stringer RN, Jurkovicova-Tarabova B, Souza IA, et al. De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy. Mol Brain, 2021, 14(1): 126.
27. Eckle VS, Shcheglovitov A, Vitko I, et al. Mechanisms by which a CACNA1H mutation in epilepsy patients increases seizure susceptibility. J Physiol, 2014, 592(4): 795-809.
28. Zamponi GW. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat Rev Drug Discov, 2016, 15(1): 19-34.
29. Zhong X, Liu JR, Kyle JW, et al. A profile of alternative RNA splicing and transcript variation of CACNA1H, a human T-channel gene candidate for idiopathic generalized epilepsies. Hum Mol Genet, 2006, 15(9): 1497-1512.
30. Becker AJ, Pitsch J, Sochivko D, et al. Transcriptional upregulation of Cav3. 2 mediates epileptogenesis in the pilocarpine model of epilepsy. J Neurosci, 2008, 28(49): 13341-13353.
31. Proft J, Rzhepetskyy Y, Lazniewska J, et al. The CACNA1H mutation in the GAERS model of absence epilepsy enhances T-type Ca(2+) currents by altering calnexin-dependent trafficking of Ca(v)3. 2 channels. Sci Rep, 2017, 7(1): 11513.
32. Kann O, Kovács R, Njunting M, et al. Metabolic dysfunction during neuronal activation in the ex vivo hippocampus from chronic epileptic rats and humans . Brain, 2005, 128(Pt 10): 2396-2407.
33. Wang G, Bochorishvili G, Chen Y, et al. CaV3. 2 calcium channels control NMDA receptor-mediated transmission:a new mechanism for absence epilepsy. Genes Dev, 2015, 29(14): 1535-1551.
34. De La Torre-Ubieta L, Won H, Stein JL, et al. Advancing the understanding of autism disease mechanisms through genetics. Nat Med, 2016, 22(4): 345-361.
35. Liao X, Li Y. Genetic associations between voltage-gated calcium channels and autism spectrum disorder: a systematic review. Mol Brain, 2020, 13(1): 96.
36. Huang IY, Hsu YL, Chen CC, et al. Excavatolide-B enhances contextual memory retrieval via repressing the delayed rectifier potassium current in the hippocampus. Mar Drugs, 2018, 16(11): 405.
37. Splawski I, Yoo DS, Stotz SC, et al. CACNA1H mutations in autism spectrum disorders. J Biol Chem, 2006, 281(31): 22085-22091.
38. Long S, Zhou H, Li S, et al. The clinical and genetic features of co-occurring epilepsy and autism spectrum disorder in Chinese children. Front Neurol, 2019, 10: 505.
39. Rzhepetskyy Y, Lazniewska J, Blesneac I, et al. CACNA1H missense mutations associated with amyotrophic lateral sclerosis alter Cav3. 2 T-type calcium channel activity and reticular thalamic neuron firing. Channels (Austin), 2016, 10(6): 466-477.
40. Steinberg KM, Yu B, Koboldt DC, et al. Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS. Sci Rep, 2015, 5: 9124.
41. Stringer RN, Jurkovicova-Tarabova B, Huang S, et al. A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Ca(v)3. 2 T-type channel activity. Mol Brain, 2020, 13(1): 33.
42. Sharma KR, Sheriff S, Maudsley A, et al. Diffusion tensor imaging of basal ganglia and thalamus in amyotrophic lateral sclerosis. J Neuroimaging, 2013, 23(3): 368-374.
43. Park SB, Kiernan MC, Vucic S. Axonal excitability in amyotrophic lateral sclerosis: axonal excitability in ALS. Neurotherapeutics, 2017, 14(1): 78-90.
44. Liu Z, Yuan Y, Wang M, et al. Mutation spectrum of amyotrophic lateral sclerosis in Central South China. Neurobiol Aging, 2021, 107: 181-188.
45. Carter MT, Mcmillan HJ, Tomin A, et al. Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy. Channels (Austin), 2019, 13(1): 153-161.
46. Souza IA, Gandini MA, Zamponi GW. Splice-variant specific effects of a CACNA1H mutation associated with writer's cramp. Mol Brain, 2021, 14(1): 145.
47. Powell KL, Cain SM, Ng C, et al. A Cav3. 2 T-type calcium channel point mutation has splice-variant-specific effects on function and segregates with seizure expression in a polygenic rat model of absence epilepsy. J Neurosci, 2009, 29(2): 371-380.
48. Calhoun JD, Huffman AM, Bellinski I, et al. CACNA1H variants are not a cause of monogenic epilepsy. Hum Mutat, 2020, 41(6): 1138-1144.
49. Itcho K, Oki K, Ohno H, et al. Update on genetics of primary aldosteronism. Biomedicines, 2021, 9(4): 409.
50. Falcón D, González MR, Sánchez DDPE, et al. Dexamethasone-induced upregulation of Ca(V)3. 2 T-type Ca(2+) channels in rat cardiac myocytes. J Steroid Biochem Mol Biol, 2018, 178: 193-202.

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