DEPDC5 基因突变与癫痫_Journal of Epilepsy

Authors：

魏子涵 , 乔晓枝 ,  邓艳春

空军军医大学西京医院神经内科（西安 710032）;

Corresponding author：

邓艳春, Email: yanchund@fmmu.edu.cn

Keywords：

DEPDC5; 癫痫; mTOR 通路; 治疗

DOI：

10.7507/2096-0247.20190072

Video：

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mTOR 通路对于神经元活性和大脑发育有重要作用，其活性异常与癫痫发生有很大的相关性。DEPDC5 是 mTOR 通路的重要组成之一，其最早发现是家族性可变灶局灶性癫痫的主要病因，随着基因测序技术的发展，常染色体显性夜间额叶癫痫和家族性颞叶癫痫等家族性局灶性癫痫、Rolandic 癫痫以及散发性局灶性癫痫也被发现与 DEPDC5 突变相关。近期发现 DEPDC5 也可能与全面性癫痫相关。文献报道 DEPDC5 相关癫痫较为难治，部分患者伴有局灶性皮质发育不良、半侧巨脑畸形，但具体机制尚不明确。DEPDC5 突变可能增加癫痫意外猝死的发生率。体内实验发现 DEPDC5 的功能对于胚胎生长和大脑的发育具有重要的作用。体内外研究表明 DEPDC5 突变是通过增加 mTOR 通路的活性影响神经元形态及活性导致癫痫发生的。mTOR 通路抑制剂西罗莫司和依维莫司以及 DEPDC5 结构类似物或 DEPDC5 功能增效剂可能会改善 DEPDC5 相关癫痫的预后。此外，生酮饮食能降低 mTORC1 活性，可能对于 DEPDC5 相关癫痫的治疗有较好的效果。文章将总结 DEPDC5 相关癫痫的表型，分析其致病机制并探讨可能的有效治疗。

Citation： 魏子涵, 乔晓枝, 邓艳春. DEPDC5 基因突变与癫痫. Journal of Epilepsy, 2019, 5(6): 450-453. doi: 10.7507/2096-0247.20190072 Copy

1.	Striano P, Zara F. Epilepsy: Common and rare epilepsies share genetic determinants. Nat Rev Neurol, 2017, 13(4): 200-201.
2.	Demarest ST, Brooks-Kayal A. From molecules to medicines: the dawn of targeted therapies for genetic epilepsies. Nat Rev Neurol, 2018, 14(12): 735-745.
3.	Xiong L, Labuda M, Li DS, et al. Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12. Am J Hum Genet, 1999, 65(6): 1698-1710.
4.	Dibbens LM, de Vries B, Donatello S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet, 2013, 45(5): 546-551.
5.	Ishida S, Picard F, Rudolf G, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet, 2013, 45(5): 552-555.
6.	Martin C, Meloche C, Rioux MF, et al. A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population. Clin Genet, 2014, 86(6): 570-574.
7.	Tsai MH, Chan CK, Chang YC, et al. DEPDC5 mutations in familial and sporadic focal epilepsy. Clin Genet, 2017, 92(4): 397-404.
8.	Picard F, Makrythanasis P, Navarro V, et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology, 2014, 82(23): 2101-2106.
9.	Picard S, Serioli E, Santulli L, et al. DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy. Epilepsia, 2015, 56(10): e168-e171.
10.	Pippucci T, Licchetta L, Baldassari S, et al. Epilepsy with auditory features: A heterogeneous clinico-molecular disease. Neurol Genet, 2015, 1(1): e5.
11.	Xiong W, Zhou D. Progress in unraveling the genetic etiology of rolandic epilepsy. Seizure, 2017, 47: 99-104.
12.	Lal D, Reinthaler EM, Schubert J, et al. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol, 2014, 75(5): 788-792.
13.	Baldassari S, Picard F, Verbeek NE, et al. The landscape of epilepsy-related GATOR1 variants. Genetics in medicine, 2019, 21(2): 398-408.
14.	Cen Z, Guo Y, Lou Y, et al. De novo mutation in DEPDC5 associated with unilateral pachygyria and intractable epilepsy. Seizure, 2017, 50: 1-3.
15.	Baulac S, Ishida S, Marsan E, et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol, 2015, 77(4): 675-683.
16.	Scheffer IE, Heron SE, Regan BM, et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol, 2014, 75(5): 782-787.
17.	Scerri T, Riseley JR, Gillies G, et al. Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol, 2015, 2(5): 575-580.
18.	Ricos MG, Hodgson BL, Pippucci T, et al. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol, 2016, 79(1): 120-131.
19.	Weckhuysen S, Marsan E, Lambrecq V, et al. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia, 2016, 57(6): 994-1003.
20.	Mirzaa GM, Campbell CD, Solovieff N, et al. Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. JAMA Neurol, 2016, 73(7): 836-845.
21.	Ribierre T, Deleuze C, Bacq A, et al. Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. J Clin Invest, 2018, 128(6): 2452-2458.
22.	Neligan A, Bell GS, Johnson AL, et al. The long-term risk of premature mortality in people with epilepsy. Brain, 2011, 134(Pt 2): 388-395.
23.	Goldman AM, Behr ER, Semsarian C, et al. Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention. Epilepsia, 2016, 57(Suppl 1): 17-25.
24.	Nascimento FA, Borlot F, Cossette P, et al. Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation. Neurol Genet, 2015, 1(4): e28.
25.	Bagnall RD, Crompton DE, Petrovski S, et al. Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. Ann Neurol, 2016, 79(4): 522-534.
26.	Shen K, Huang RK, Brignole EJ, et al. Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes. Nature, 2018, 556(7699): 64-69.
27.	Baulac S. mTOR signaling pathway genes in focal epilepsies. Prog Brain Res, 2016, 226: 61-79.
28.	Francesca L C, Nathaniel H. Role of mTOR Complexes in Neurogenesis. International Journal of Molecular Sciences, 2018, 19(5): 1544-1559.
29.	van Kranenburg M, Hoogeveen-Westerveld M, Nellist M. Preliminary functional assessment and classification of DEPDC5 variants associated with focal epilepsy. Hum Mutat, 2015, 36(2): 200-209.
30.	Iffland PH 2nd, Baybis M, Barnes AE, et al. DEPDC5 and NPRL3 modulate cell size, filopodial outgrowth, and localization of mTOR in neural progenitor cells and neurons. Neurobiol Dis, 2018, 114: 184-193.
31.	Marsan E, Ishida S, Schramm A, et al. Depdc5 knockout rat: A novel model of mTORopathy. Neurobiol Dis, 2016, 89: 180-189.
32.	Yuskaitis CJ, Jones BM, Wolfson RL, et al. A mouse model of DEPDC5-related epilepsy: Neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility. Neurobiol Dis, 2018, 111: 91-101.
33.	de Calbiac H, Dabacan A, Marsan E, et al. Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish. Ann Clin Transl Neurol, 2018, 5(5): 510-523.
34.	Drion CM, van Scheppingen J, Arena A, et al. Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo - in search of potential anti-epileptogenic strategies for temporal lobe epilepsy. J Neuroinflammation, 2018, 15(1): 212.
35.	Parker WE, Orlova KA, Parker WH, et al. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med, 2013, 5(182): 182ra53.
36.	Wheless JW. Use of the mTOR inhibitor everolimus in a patient with multiple manifestations of tuberous sclerosis complex including epilepsy. Epilepsy Behav Case Rep, 2015, 4: 63-66.
37.	Myers KA, Scheffer IE. DEPDC5 as a potential therapeutic target for epilepsy. Expert OpinTher Targets, 2017, 21(6): 591-600.
38.	McDaniel SS, Rensing NR, Thio LL, et al. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia, 2011, 52(3): e7-e11.
39.	Curatolo P, Moavero R. mTOR inhibitors as a new therapeutic option for epilepsy. Expert Rev Neurother, 2013, 13(6): 627-638.

1. Striano P, Zara F. Epilepsy: Common and rare epilepsies share genetic determinants. Nat Rev Neurol, 2017, 13(4): 200-201.
2. Demarest ST, Brooks-Kayal A. From molecules to medicines: the dawn of targeted therapies for genetic epilepsies. Nat Rev Neurol, 2018, 14(12): 735-745.
3. Xiong L, Labuda M, Li DS, et al. Mapping of a gene determining familial partial epilepsy with variable foci to chromosome 22q11-q12. Am J Hum Genet, 1999, 65(6): 1698-1710.
4. Dibbens LM, de Vries B, Donatello S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet, 2013, 45(5): 546-551.
5. Ishida S, Picard F, Rudolf G, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet, 2013, 45(5): 552-555.
6. Martin C, Meloche C, Rioux MF, et al. A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population. Clin Genet, 2014, 86(6): 570-574.
7. Tsai MH, Chan CK, Chang YC, et al. DEPDC5 mutations in familial and sporadic focal epilepsy. Clin Genet, 2017, 92(4): 397-404.
8. Picard F, Makrythanasis P, Navarro V, et al. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology, 2014, 82(23): 2101-2106.
9. Picard S, Serioli E, Santulli L, et al. DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy. Epilepsia, 2015, 56(10): e168-e171.
10. Pippucci T, Licchetta L, Baldassari S, et al. Epilepsy with auditory features: A heterogeneous clinico-molecular disease. Neurol Genet, 2015, 1(1): e5.
11. Xiong W, Zhou D. Progress in unraveling the genetic etiology of rolandic epilepsy. Seizure, 2017, 47: 99-104.
12. Lal D, Reinthaler EM, Schubert J, et al. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol, 2014, 75(5): 788-792.
13. Baldassari S, Picard F, Verbeek NE, et al. The landscape of epilepsy-related GATOR1 variants. Genetics in medicine, 2019, 21(2): 398-408.
14. Cen Z, Guo Y, Lou Y, et al. De novo mutation in DEPDC5 associated with unilateral pachygyria and intractable epilepsy. Seizure, 2017, 50: 1-3.
15. Baulac S, Ishida S, Marsan E, et al. Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Ann Neurol, 2015, 77(4): 675-683.
16. Scheffer IE, Heron SE, Regan BM, et al. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol, 2014, 75(5): 782-787.
17. Scerri T, Riseley JR, Gillies G, et al. Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Ann Clin Transl Neurol, 2015, 2(5): 575-580.
18. Ricos MG, Hodgson BL, Pippucci T, et al. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol, 2016, 79(1): 120-131.
19. Weckhuysen S, Marsan E, Lambrecq V, et al. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia, 2016, 57(6): 994-1003.
20. Mirzaa GM, Campbell CD, Solovieff N, et al. Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. JAMA Neurol, 2016, 73(7): 836-845.
21. Ribierre T, Deleuze C, Bacq A, et al. Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. J Clin Invest, 2018, 128(6): 2452-2458.
22. Neligan A, Bell GS, Johnson AL, et al. The long-term risk of premature mortality in people with epilepsy. Brain, 2011, 134(Pt 2): 388-395.
23. Goldman AM, Behr ER, Semsarian C, et al. Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention. Epilepsia, 2016, 57(Suppl 1): 17-25.
24. Nascimento FA, Borlot F, Cossette P, et al. Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation. Neurol Genet, 2015, 1(4): e28.
25. Bagnall RD, Crompton DE, Petrovski S, et al. Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. Ann Neurol, 2016, 79(4): 522-534.
26. Shen K, Huang RK, Brignole EJ, et al. Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes. Nature, 2018, 556(7699): 64-69.
27. Baulac S. mTOR signaling pathway genes in focal epilepsies. Prog Brain Res, 2016, 226: 61-79.
28. Francesca L C, Nathaniel H. Role of mTOR Complexes in Neurogenesis. International Journal of Molecular Sciences, 2018, 19(5): 1544-1559.
29. van Kranenburg M, Hoogeveen-Westerveld M, Nellist M. Preliminary functional assessment and classification of DEPDC5 variants associated with focal epilepsy. Hum Mutat, 2015, 36(2): 200-209.
30. Iffland PH 2nd, Baybis M, Barnes AE, et al. DEPDC5 and NPRL3 modulate cell size, filopodial outgrowth, and localization of mTOR in neural progenitor cells and neurons. Neurobiol Dis, 2018, 114: 184-193.
31. Marsan E, Ishida S, Schramm A, et al. Depdc5 knockout rat: A novel model of mTORopathy. Neurobiol Dis, 2016, 89: 180-189.
32. Yuskaitis CJ, Jones BM, Wolfson RL, et al. A mouse model of DEPDC5-related epilepsy: Neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility. Neurobiol Dis, 2018, 111: 91-101.
33. de Calbiac H, Dabacan A, Marsan E, et al. Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish. Ann Clin Transl Neurol, 2018, 5(5): 510-523.
34. Drion CM, van Scheppingen J, Arena A, et al. Effects of rapamycin and curcumin on inflammation and oxidative stress in vitro and in vivo - in search of potential anti-epileptogenic strategies for temporal lobe epilepsy. J Neuroinflammation, 2018, 15(1): 212.
35. Parker WE, Orlova KA, Parker WH, et al. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med, 2013, 5(182): 182ra53.
36. Wheless JW. Use of the mTOR inhibitor everolimus in a patient with multiple manifestations of tuberous sclerosis complex including epilepsy. Epilepsy Behav Case Rep, 2015, 4: 63-66.
37. Myers KA, Scheffer IE. DEPDC5 as a potential therapeutic target for epilepsy. Expert OpinTher Targets, 2017, 21(6): 591-600.
38. McDaniel SS, Rensing NR, Thio LL, et al. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia, 2011, 52(3): e7-e11.
39. Curatolo P, Moavero R. mTOR inhibitors as a new therapeutic option for epilepsy. Expert Rev Neurother, 2013, 13(6): 627-638.

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