突觸融合蛋白結合蛋白-1 基因相關腦病的臨床表型及基因研究進展_Journal of Epilepsy

Authors：

馬娛 ¹ ,  王藝 ^1,2

1. ;
2. ;

Corresponding?author：

王藝, Email: yiwang@shmu.edu.cn

Keywords：

癲癇性腦病; STXBP1 基因; 動物模型; 臨床表型

DOI：

10.7507/2096-0247.20180038

Video：

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癲癇性腦病是嬰兒期和兒童早期嚴重的腦部疾患，其中 70% 癲癇性腦病與遺傳因素相關。突觸融合蛋白結合蛋白-1（Syntaxin-binding protein 1，STXBP1）基因編碼 STXBP1，其發生突變可影響突觸囊泡融合及神經遞質釋放，是引起癲癇性腦病的常見致病基因。STXBP1 基因突變的致病機制是單倍劑量不足，STXBP1 的補充或激活可能是一種潛在的精準治療策略。文章對近年來報道的 STXBP1 基因相關腦病的臨床表型、基因研究等進展進行綜述。

Citation： 馬娛, 王藝. 突觸融合蛋白結合蛋白-1 基因相關腦病的臨床表型及基因研究進展. Journal of Epilepsy, 2018, 4(3): 220-223. doi: 10.7507/2096-0247.20180038 Copy

1.	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.
2.	Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on classification and terminology, 2005-2009. Epilepsia, 2010, 51(4): 676-685.
3.	Hildebrand MS, Dahl HH, Damiano JA, et al. Recent advances in the molecular genetics of epilepsy. J Med Genet, 2013, 50(5): 271-279.
4.	Mastrangelo M. Novel genes of early-onset epileptic encephalopathies: From genotype to phenotypes. Pediatr Neurol, 2015, 53(2): 119-129.
5.	Romaniello R, Zucca C, Tenderini E, et al. A novel mutation in STXBP1 gene in a child with epileptic encephalopathy and an atypical electroclinical pattern. J Child Neurol, 2014, 29(2): 249-253.
6.	Butler KM, Da SC, Alexander JJ, et al. Diagnostic yield erom 339 epilepsy patients screened on a clinical gene panel. Pediatr Neurol, 2017, 77: 61-66.
7.	Hamdan FF, Piton A, Gauthier J, et al. De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy. Ann Neurol, 2009, 65(6): 748-753.
8.	Stamberger H, Weckhuysen S, de Jonghe P. STXBP1 as a therapeutic target for epileptic encephalopathy. Expert Opin Ther Targets, 2017, 21(11): 1027-1036.
9.	Han J, Pluhackova K, Bockmann RA. The multifaceted role of SNARE proteins in membrane fusion. Front Physiol, 2017, 8: 5.
10.	Ma C, Li W, Xu Y, et al. Munc13 mediates the transition from the closed syntaxin-munc18 complex to the SNARE complex. Nat Struct Mol Biol, 2011, 18(5): 542-549.
11.	Martin S, Tomatis VM, Papadopulos A, et al. The munc18-1 domain 3a loop is essential for neuroexocytosis but not for syntaxin-1A transport to the plasma membrane. J Cell Sci, 2013, 126(11): 2353-2360.
12.	Yamamoto T, Shimojima K, Yano T, et al. Loss-of-function mutations of STXBP1 in patients with epileptic encephalopathy. Brain Dev, 2016, 38(3): 280-284.
13.	Suri M, Evers J, Laskowski RA, et al. Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1. Mol Genet Genomic Med, 2017, 5(5): 495-507.
14.	Shyu A, Wilkinson MF, van Hoof A. Messenger RNA regulation: to translate or to degrade. The Embo Journal, 2008, 27(3): 471-481.
15.	Nasif S, Contu L, Muhlemann O. Beyond quality control: The role of nonsense-mediated mRNA decay (NMD) in regulating gene expression. Semin Cell Dev Biol, 2017, S1084-9521(17): 30342-30347.
16.	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.
17.	Miyamoto H, Shimohata A, Abe M, et al. Potentiation of excitatory synaptic transmission ameliorates aggression in mice with STXBP1 haploinsufficiency. Hum Mol Genet, 2017, 26(24): 4961-4974.
18.	Ohtahara S, Yamatogi Y. Ohtahara syndrome: with special reference to its developmental aspects for differentiating from early myoclonic encephalopathy. Epilepsy Res, 2006, 70: 58-67.
19.	Paolicchi JM, Ross G, Lee D, et al. Clobazam and aggression-related adverse events in pediatric patients with lennox-gastaut syndrome. Pediatr Neurol, 2015, 53(4): 338-342.
20.	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): 1511-15148.
21.	Yamashita S, Chiyonobu T, Yoshida M, et al. Mislocalization of syntaxin-1 and impaired neurite growth observed in a human iPSC model for STXBP1-related epileptic encephalopathy. Epilepsia, 2016, 57(4): 81-86.
22.	Stamberger H, Nikanorova M, Willemsen MH, et al. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. Neurology, 2016, 86(10): 954-962.
23.	Djukic A, Lado FA, Shinnar S, et al. Are early myoclonic encephalopathy (EME) and the ohtahara syndrome (EIEE) independent of each other?. Epilepsy Res, 2006, 70 (Suppl 1): 68-76.
24.	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.
25.	Milh M, Villeneuve N, Chouchane M, et al. Epileptic and nonepileptic features in patients with early onset epileptic encephalopathy and STXBP1 mutations. Epilepsia, 2011, 52(10): 1828-1834.
26.	Olson HE, Kelly M, Lacoursiere CM, et al. Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression. Ann Neurol, 2017, 81(3): 419-429.
27.	Otsuka M, Oguni H, Liang JS, et al. STXBP1 mutations cause not only ohtahara syndrome but also west syndrome--result of japanese cohort study. Epilepsia, 2010, 51(12): 2449-2452.
28.	Deprez L, Weckhuysen S, Holmgren P, et al. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology, 2010, 75(13): 1159-1165.
29.	Boutry-Kryza N, Labalme A, Ville D, et al. Molecular characterization of a cohort of 73 patients with infantile spasms syndrome. Eur J Med Genet, 2015, 58(2): 51-58.
30.	Michaud JL, lachance M, Hamdan FF, et al. The genetic landscape of infantile spasms. Hum Mol Genet, 2014, 23(18): 4846-4858.
31.	Allen AS, Berkovic SF, Cossette P, et al. De novo mutations in epileptic encephalopathies. Nature, 2013, 501(7466): 217-221.
32.	Mignot C, Moutard ML, Trouillard O, et al. STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients. Epilepsia, 2011, 52(10): 1820-1827.
33.	Steel D, Symonds JD, Zuberi SM, et al. Dravet syndrome and its mimics: Beyond SCN1A. Epilepsia, 2017, 58(11): 1807-1816.
34.	Carvill GL, Weckhuysen S, Mcmahon JM, et al. GABRA1 and STXBP1: Novel genetic causes of dravet syndrome. Neurology, 2014, 82(14): 1245-1253.
35.	Mastrangelo M. Lennox-gastaut syndrome: A state of the art review. Neuropediatrics, 2017, 48(3): 143-151.
36.	Tso WW, Kwong AK, Fung CW, et al. Folinic acid responsive epilepsy in ohtahara syndrome caused by STXBP1 mutation. Pediatr Neurol, 2014, 50(2): 177-180.
37.	Hussain S. Developing a PPI inhibitor-based therapy for STXBP1 haploinsufficiency-associated epileptic disorders. Front Mol Neurosci, 2014, 7: 6.

1. 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.
2. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on classification and terminology, 2005-2009. Epilepsia, 2010, 51(4): 676-685.
3. Hildebrand MS, Dahl HH, Damiano JA, et al. Recent advances in the molecular genetics of epilepsy. J Med Genet, 2013, 50(5): 271-279.
4. Mastrangelo M. Novel genes of early-onset epileptic encephalopathies: From genotype to phenotypes. Pediatr Neurol, 2015, 53(2): 119-129.
5. Romaniello R, Zucca C, Tenderini E, et al. A novel mutation in STXBP1 gene in a child with epileptic encephalopathy and an atypical electroclinical pattern. J Child Neurol, 2014, 29(2): 249-253.
6. Butler KM, Da SC, Alexander JJ, et al. Diagnostic yield erom 339 epilepsy patients screened on a clinical gene panel. Pediatr Neurol, 2017, 77: 61-66.
7. Hamdan FF, Piton A, Gauthier J, et al. De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy. Ann Neurol, 2009, 65(6): 748-753.
8. Stamberger H, Weckhuysen S, de Jonghe P. STXBP1 as a therapeutic target for epileptic encephalopathy. Expert Opin Ther Targets, 2017, 21(11): 1027-1036.
9. Han J, Pluhackova K, Bockmann RA. The multifaceted role of SNARE proteins in membrane fusion. Front Physiol, 2017, 8: 5.
10. Ma C, Li W, Xu Y, et al. Munc13 mediates the transition from the closed syntaxin-munc18 complex to the SNARE complex. Nat Struct Mol Biol, 2011, 18(5): 542-549.
11. Martin S, Tomatis VM, Papadopulos A, et al. The munc18-1 domain 3a loop is essential for neuroexocytosis but not for syntaxin-1A transport to the plasma membrane. J Cell Sci, 2013, 126(11): 2353-2360.
12. Yamamoto T, Shimojima K, Yano T, et al. Loss-of-function mutations of STXBP1 in patients with epileptic encephalopathy. Brain Dev, 2016, 38(3): 280-284.
13. Suri M, Evers J, Laskowski RA, et al. Protein structure and phenotypic analysis of pathogenic and population missense variants in STXBP1. Mol Genet Genomic Med, 2017, 5(5): 495-507.
14. Shyu A, Wilkinson MF, van Hoof A. Messenger RNA regulation: to translate or to degrade. The Embo Journal, 2008, 27(3): 471-481.
15. Nasif S, Contu L, Muhlemann O. Beyond quality control: The role of nonsense-mediated mRNA decay (NMD) in regulating gene expression. Semin Cell Dev Biol, 2017, S1084-9521(17): 30342-30347.
16. 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.
17. Miyamoto H, Shimohata A, Abe M, et al. Potentiation of excitatory synaptic transmission ameliorates aggression in mice with STXBP1 haploinsufficiency. Hum Mol Genet, 2017, 26(24): 4961-4974.
18. Ohtahara S, Yamatogi Y. Ohtahara syndrome: with special reference to its developmental aspects for differentiating from early myoclonic encephalopathy. Epilepsy Res, 2006, 70: 58-67.
19. Paolicchi JM, Ross G, Lee D, et al. Clobazam and aggression-related adverse events in pediatric patients with lennox-gastaut syndrome. Pediatr Neurol, 2015, 53(4): 338-342.
20. 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): 1511-15148.
21. Yamashita S, Chiyonobu T, Yoshida M, et al. Mislocalization of syntaxin-1 and impaired neurite growth observed in a human iPSC model for STXBP1-related epileptic encephalopathy. Epilepsia, 2016, 57(4): 81-86.
22. Stamberger H, Nikanorova M, Willemsen MH, et al. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. Neurology, 2016, 86(10): 954-962.
23. Djukic A, Lado FA, Shinnar S, et al. Are early myoclonic encephalopathy (EME) and the ohtahara syndrome (EIEE) independent of each other?. Epilepsy Res, 2006, 70 (Suppl 1): 68-76.
24. 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.
25. Milh M, Villeneuve N, Chouchane M, et al. Epileptic and nonepileptic features in patients with early onset epileptic encephalopathy and STXBP1 mutations. Epilepsia, 2011, 52(10): 1828-1834.
26. Olson HE, Kelly M, Lacoursiere CM, et al. Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression. Ann Neurol, 2017, 81(3): 419-429.
27. Otsuka M, Oguni H, Liang JS, et al. STXBP1 mutations cause not only ohtahara syndrome but also west syndrome--result of japanese cohort study. Epilepsia, 2010, 51(12): 2449-2452.
28. Deprez L, Weckhuysen S, Holmgren P, et al. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology, 2010, 75(13): 1159-1165.
29. Boutry-Kryza N, Labalme A, Ville D, et al. Molecular characterization of a cohort of 73 patients with infantile spasms syndrome. Eur J Med Genet, 2015, 58(2): 51-58.
30. Michaud JL, lachance M, Hamdan FF, et al. The genetic landscape of infantile spasms. Hum Mol Genet, 2014, 23(18): 4846-4858.
31. Allen AS, Berkovic SF, Cossette P, et al. De novo mutations in epileptic encephalopathies. Nature, 2013, 501(7466): 217-221.
32. Mignot C, Moutard ML, Trouillard O, et al. STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients. Epilepsia, 2011, 52(10): 1820-1827.
33. Steel D, Symonds JD, Zuberi SM, et al. Dravet syndrome and its mimics: Beyond SCN1A. Epilepsia, 2017, 58(11): 1807-1816.
34. Carvill GL, Weckhuysen S, Mcmahon JM, et al. GABRA1 and STXBP1: Novel genetic causes of dravet syndrome. Neurology, 2014, 82(14): 1245-1253.
35. Mastrangelo M. Lennox-gastaut syndrome: A state of the art review. Neuropediatrics, 2017, 48(3): 143-151.
36. Tso WW, Kwong AK, Fung CW, et al. Folinic acid responsive epilepsy in ohtahara syndrome caused by STXBP1 mutation. Pediatr Neurol, 2014, 50(2): 177-180.
37. Hussain S. Developing a PPI inhibitor-based therapy for STXBP1 haploinsufficiency-associated epileptic disorders. Front Mol Neurosci, 2014, 7: 6.

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突觸融合蛋白結合蛋白-1 基因相關腦病的臨床表型及基因研究進展

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