突触融合蛋白结合蛋白 1 基因与癫痫性脑病的研究进展_Journal of Epilepsy

Authors：

刘梅歌 , 李亚静 , 赵春维 , 肖丹青 , 董伟伟 , 刘扬 ,  刘献增

Corresponding author：

刘献增, Email: liuxianzeng2004@sina.com

Keywords：

癫痫性脑病; 突触融合蛋白结合蛋白 1; 可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体蛋白

DOI：

10.7507/2096-0247.20180070

Video：

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癫痫性脑病（Epileptic encephalopathy，EE）是一类由难治性癫痫极度异常脑电活动导致的脑部疾病。近年来随着分子遗传学的进步，越来越多的研究表明突触融合蛋白结合蛋白 1（Synaptotagmin binding protein 1, STXBP1）基因突变与 EE 有关。文章对 EE 的病因及病理生理学机制进行综述，从而提高临床医生对 EE 的认识，并探讨将 STXBP1 作为靶点治疗 EE 的可能性，为临床治疗 EE 提供依据和指导。

Citation： 刘梅歌, 李亚静, 赵春维, 肖丹青, 董伟伟, 刘扬, 刘献增. 突触融合蛋白结合蛋白 1 基因与癫痫性脑病的研究进展. Journal of Epilepsy, 2018, 4(5): 421-425. doi: 10.7507/2096-0247.20180070 Copy

1.	Ma L, Rebane AA, Yang G, et al. Munc18-1-regulated stage-wise SNARE assembly underlying synaptic exocytosis. Elife, 2015, 4: e09580.
2.	Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
3.	Eltze CM, Chong WK, Cox T, et al. A population-based study of newly diagnosed epilepsy in infants. Epilepsia, 2013, 54(3): 437-445.
4.	McTague A, Howell KB, Cross JH, et al. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol, 2016, 15(3): 304-316.
5.	Wang J, Lin ZJ, Liu L, et al. Epilepsy-associated genes. Seizure, 2017, 44: 11-20.
6.	Saitsu H, Kato M, Mizuguchi T, et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet, 2008, 40(6): 782-788.
7.	Romaniello R, Saettini F, Panzeri E, et al. A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype. Neuroreport, 2015, 26(5): 254-257.
8.	Hamdan FF, Srour M, Capo-Chichi JM, et al. De novo mutations in moderate or severe intellectual disability. , 2014, 10(10): e1004772.
9.	Stamberger H, Nikanorova M, Willemsen MH, et al. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. Neurology, 2016, 86(10): 954-962.
10.	Rizo J, Xu J. The synaptic vesicle release machinery. Annu Rev Biophys, 2015, 44: 339-367.
11.	Han J, Pluhackova K, Böckmann RA, et al. The multifaceted role of SNARE proteins in membrane fusion. Front Physiol, 2017, 8: 5.
12.	Ryu JK, Jahn R, Yoon TY. Review: Progresses in understanding N-ethylmaleimide sensitive factor (NSF) mediated disassembly of SNARE complexes. Biopolymers, 2016, 105(8): 518-531.
13.	Ma C, Su L, Seven AB, et al. Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release. Science, 2013, 339(6118): 421-425.
14.	Kavanagh DM, Smyth AM, Martin KJ, et al. A molecular toggle after exocytosis sequesters the presynaptic syntaxin1a molecules involved in prior vesicle fusion. Nat Commun, 2014, 5: 5774.
15.	Carvill GL, Weckhuysen S, McMahon JM, et al. GABRA1 and STXBP1: novel genetic causes of dravet syndrome. Neurology, 2014, 82(14): 1245-1253.
16.	Toonen RF, Wierda K, Sons MS, et al. Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size. Proc Natl Acad Sci USA, 2006, 103(48): 18332-18337.
17.	Martin S, Papadopulos A, Tomatis VM, et al. Increased polyubiquitination and proteasomal degradation of a Munc18-1 disease-linked mutant causes temperature-sensitive defect in exocytosis. Cell Rep, 2014, 9(1): 206-218.
18.	Chai YJ, Sierecki E, Tomatis VM, et al. Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation. J Cell Biol, 2016, 214(6): 705-718.
19.	Hager T, Maroteaux G, Pont PD, et al. Munc18-1 haploinsufficiency results in enhanced anxiety-like behavior as determined by heart rate responses in mice. Behav Brain Res, 2014, 260: 44-52.
20.	Shen C, Rathore SS, Yu H, et al. The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis. Nat Commun, 2015, 6: 8852.
21.	Grone BP, Marchese M, Hamling KR, et al. Epilepsy, behavioral abnormalities, and physiological comorbidities in syntaxin-binding protein 1 (STXBP1) mutant zebrafish. PLoS One, 2016, 11(3): e0151148.
22.	Gburek-Augustat J, Beck-Woedl S, Tzschach A, et al. Epilepsy is not a mandatory feature of STXBP1 associated ataxia-tremor-retardation syndrome. Eur J Paediatr Neurol, 2016, 20(4): 661-665.
23.	Sivaraju A, Nussbaum I, Cardoza CS, et al. Substantial and sustained seizure reduction with ketogenic diet in a patient with ohtahara syndrome. Epilepsy Behav Case Rep, 2015, 3: 43-45.
24.	Patzke C, Han Y, Covy J, et al. Analysis of conditional heterozygous STXBP1 mutations in human neurons. J Clin Invest, 2015, 125(9): 3560-3571.
25.	Verhage M, Maia AS, Plomp JJ, et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science, 2000, 287(5454): 864-869.
26.	Netrakanti PR, Cooper BH, Dere E, et al. Fast cerebellar reflex circuitry requires synaptic vesicle priming by munc13-3. Cerebellum, 2015, 14(3): 264-283.
27.	Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA, 2004, 101(26): 9861-9866.
28.	Pierson TM, Yuan H, Marsh ED, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol, 2014, 1(3): 190-198.
29.	Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet, 2016, 2(5): e96.

1. Ma L, Rebane AA, Yang G, et al. Munc18-1-regulated stage-wise SNARE assembly underlying synaptic exocytosis. Elife, 2015, 4: e09580.
2. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 2017, 58(4): 512-521.
3. Eltze CM, Chong WK, Cox T, et al. A population-based study of newly diagnosed epilepsy in infants. Epilepsia, 2013, 54(3): 437-445.
4. McTague A, Howell KB, Cross JH, et al. The genetic landscape of the epileptic encephalopathies of infancy and childhood. Lancet Neurol, 2016, 15(3): 304-316.
5. Wang J, Lin ZJ, Liu L, et al. Epilepsy-associated genes. Seizure, 2017, 44: 11-20.
6. Saitsu H, Kato M, Mizuguchi T, et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet, 2008, 40(6): 782-788.
7. Romaniello R, Saettini F, Panzeri E, et al. A de-novo STXBP1 gene mutation in a patient showing the Rett syndrome phenotype. Neuroreport, 2015, 26(5): 254-257.
8. Hamdan FF, Srour M, Capo-Chichi JM, et al. De novo mutations in moderate or severe intellectual disability. , 2014, 10(10): e1004772.
9. Stamberger H, Nikanorova M, Willemsen MH, et al. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. Neurology, 2016, 86(10): 954-962.
10. Rizo J, Xu J. The synaptic vesicle release machinery. Annu Rev Biophys, 2015, 44: 339-367.
11. Han J, Pluhackova K, Böckmann RA, et al. The multifaceted role of SNARE proteins in membrane fusion. Front Physiol, 2017, 8: 5.
12. Ryu JK, Jahn R, Yoon TY. Review: Progresses in understanding N-ethylmaleimide sensitive factor (NSF) mediated disassembly of SNARE complexes. Biopolymers, 2016, 105(8): 518-531.
13. Ma C, Su L, Seven AB, et al. Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release. Science, 2013, 339(6118): 421-425.
14. Kavanagh DM, Smyth AM, Martin KJ, et al. A molecular toggle after exocytosis sequesters the presynaptic syntaxin1a molecules involved in prior vesicle fusion. Nat Commun, 2014, 5: 5774.
15. Carvill GL, Weckhuysen S, McMahon JM, et al. GABRA1 and STXBP1: novel genetic causes of dravet syndrome. Neurology, 2014, 82(14): 1245-1253.
16. Toonen RF, Wierda K, Sons MS, et al. Munc18-1 expression levels control synapse recovery by regulating readily releasable pool size. Proc Natl Acad Sci USA, 2006, 103(48): 18332-18337.
17. Martin S, Papadopulos A, Tomatis VM, et al. Increased polyubiquitination and proteasomal degradation of a Munc18-1 disease-linked mutant causes temperature-sensitive defect in exocytosis. Cell Rep, 2014, 9(1): 206-218.
18. Chai YJ, Sierecki E, Tomatis VM, et al. Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation. J Cell Biol, 2016, 214(6): 705-718.
19. Hager T, Maroteaux G, Pont PD, et al. Munc18-1 haploinsufficiency results in enhanced anxiety-like behavior as determined by heart rate responses in mice. Behav Brain Res, 2014, 260: 44-52.
20. Shen C, Rathore SS, Yu H, et al. The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis. Nat Commun, 2015, 6: 8852.
21. Grone BP, Marchese M, Hamling KR, et al. Epilepsy, behavioral abnormalities, and physiological comorbidities in syntaxin-binding protein 1 (STXBP1) mutant zebrafish. PLoS One, 2016, 11(3): e0151148.
22. Gburek-Augustat J, Beck-Woedl S, Tzschach A, et al. Epilepsy is not a mandatory feature of STXBP1 associated ataxia-tremor-retardation syndrome. Eur J Paediatr Neurol, 2016, 20(4): 661-665.
23. Sivaraju A, Nussbaum I, Cardoza CS, et al. Substantial and sustained seizure reduction with ketogenic diet in a patient with ohtahara syndrome. Epilepsy Behav Case Rep, 2015, 3: 43-45.
24. Patzke C, Han Y, Covy J, et al. Analysis of conditional heterozygous STXBP1 mutations in human neurons. J Clin Invest, 2015, 125(9): 3560-3571.
25. Verhage M, Maia AS, Plomp JJ, et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science, 2000, 287(5454): 864-869.
26. Netrakanti PR, Cooper BH, Dere E, et al. Fast cerebellar reflex circuitry requires synaptic vesicle priming by munc13-3. Cerebellum, 2015, 14(3): 264-283.
27. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA, 2004, 101(26): 9861-9866.
28. Pierson TM, Yuan H, Marsh ED, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol, 2014, 1(3): 190-198.
29. Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet, 2016, 2(5): e96.

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