神經元移行障礙發病機制研究進展_Journal of Epilepsy

Authors：

齊暉 ,  高麗 , 李巖 , 范宏業 , 楊柳 , 曹睿明 , 殷小靜 , 李俊龍

河南省人民醫院兒科(鄭州 450003);

Corresponding?author：

高麗, Email: msgaoli@126.com

Keywords：

皮質發育不良; 基因; 信號通路; 癲癇

DOI：

10.7507/2096-0247.20170066

Video：

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胚胎發育時期因各種因素引起的神經元移行障礙，常導致大腦皮質發育畸形(Malformation of cortical development，MCD)，也是引起患兒發育遲緩和癲癇的常見原因。快速發展的分子生物學、影像學和基因遺傳學豐富了大腦皮質發育的相關知識，畸形的報道不僅在數量和種類上有所增長，同時相關研究已經確定了幾個基因，可能破壞神經細胞增殖、移行以及晚期皮層組織形成的每一個重要階段。不同的MCD在臨床表現上也有很大的表型異質性，現就MCD的發生機制、易感基因進行闡述，為MCD后期研究提供參考依據。

Citation： 齊暉, 高麗, 李巖, 范宏業, 楊柳, 曹睿明, 殷小靜, 李俊龍. 神經元移行障礙發病機制研究進展. Journal of Epilepsy, 2017, 3(5): 419-422. doi: 10.7507/2096-0247.20170066 Copy

1.	Crino PB.mTOR signaling in epilepsy: insights from malformations of cortical development.Cold Spring Harb Perspect Med, 2015, 5(4): 422-442.
2.	Tischfeld MA, Cederquist GY, Gupta ML Jr, et al. Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations.Curr Opin Genet Dev, 2011, 21(3): 286-294.
3.	Han JM, Sahin M.TSC1/TSC2 signaling in the CNS.FEBS Lett, 2011, 585(7): 973-980.
4.	Crino PB.Evolving neurobiology of tuberous sclerosis complex.Acta Neuropathol, 2013, 125(3): 317-332.
5.	Riviere JB, Mirzaa GM, O'Roak BJ, et al. Finding of Rare Disease Genes (FORGE) Canada Consortium.Nat Genet, 2012, 44(8): 934-940.
6.	Jansen LA, Mirzaa GM, Ishak GE, et al. PI3K/AKT pathway mutations cause a spectrum of brain malformations frommegalencephaly to focal cortical dysplasia.Brain, 2015, 138(Pt 6): 1613-1628.
7.	Mirzaa GM, Riviere JB, Dobyns WB.Megalencephaly syndromes andactivating mutations in the PI3K-AKT pathway: MPPH and MCAP.Am JMed Genet C Semin Med Genet, 2013, 163(2): 122-130.
8.	Roy A, Skibo J, Kalume F, et al. Mouse models of human PIK3CA-relatedbrain overgrowth have acutely treatable epilepsy.Elife, 2015, 4(3): piie12703.
9.	Poduri A, Evrony GD, Cai X, et al. Somatic activationof AKT3 causes hemispheric developmental brain malformations.Neuron, 2012, 74(1): 41-48.
10.	Baek ST, Copeland B, Yun EJ, et al. An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development.Nat Med, 2015, 21(12): 1445-1454.
11.	Chang BS, Duzcan F, Kim S, et al. The role of RELN in lissencephaly and neuropsychiatric disease.Am J Med Genet B Neuropsychiatr Genet, 2007, 144(1): 58-63.
12.	Moon UY, Park JY, Park R, et al. Impaired Reelin-Dab1 signaling contributes to neuronal mig-ration defcits of tuberous sclerosis complex.Cell Rep, 2015, 12(6): 965-978.
13.	Eggers CM, Kline ER, Zhong D, et al. STE20-relatedkinase adaptor protein alpha (STRAD alpha) regulates cell polarityand invasion through PAK1 signaling in LKB1-null cells.J Biol Chem, 2012, 287(22): 18758-18768.
14.	Orlova KA, Parker WE, Heuer GG, et al. STRADalpha defciency results in aberrant mTORC1 signaling during corticogenesis in humans and mice.J ClinInvest, 2010, 120(5): 1591-1602.
15.	Parker WE, Orlova KA, Parker WH, et al. Rapamycin prevents seizures after depletion of ST-RADA in a rare neurodevelopmental disorder.Sci Transl Med, 2013, 182(5): 182ra53.
16.	Pilarski R, Stephens JA, Noss R, et al. Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features.J Med Genet, 2011, 48(8): 505-512.
17.	Ljungberg MC, Sunnen CN, Lugo JN, et al. Rapamycin suppresses seizures and neuronal hyp-ertrophy in a mousemodel of cortical dysplasia.Dis Model Mech, 2009, 2(7-8): 389-398.
18.	Mester JL, Tilot AK, Rybicki LA, et al. Analysis of prevalence and degree of macrocephaly in patients with germline PTENmutations and of brain weight in Pten knock-in murine model.Eu-r JHum Genet, 2011, 19(7): 763-768.
19.	Kwon CH, Zhu X, Zhang J, et al. mTOR is required for hypertrophyof Pten-defcient neuronal soma in vivo.Proc Natl Acad Sci USA, 2003, 100(22): 12923-12928.
20.	Sunnen CN, Brewster AL, Lugo JN, et al. Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice.Epilepsia, 2011, 52(11): 2065-2075.
21.	Bar-Peled L, Chantranupong L, Cherniack AD, et al. A Tumor suppressor complex with GAP activity for the RagGTPases that signal amino acid sufciency to mTORC1.Science, 2013, 340(6136): 1100-1106.
22.	Alfaiz AA, Micale L, Mandriani B, et al. TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease.Hum Mutat, 2014, 35(4): 447-451.
23.	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, 2015, 79(1): 120-131.
24.	Wei Y, Lilly MA.The TORC1 inhibitors Nprl2 and Nprl3 mediate anadaptive response to amino-acid starvation in Drosophila.Cell DeathDier, 2014, 21(9): 1460-1468.
25.	Choi YJ, Di NA, Kramvis I, et al. Tuberous sclerosis complex proteins control axon formation.GenesDev, 2008, 22(18): 2485-2495.
26.	Baulac S, Ishida S, Marsan E, et al. Familialfocal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.Ann Neurol, 2015, 77(4): 675-683.
27.	Chantranupong L, Wolfson RL, Orozco JM, et al. The Sestrins interactwith GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1.Cell Rep, 2014, 9(1): 1-8.
28.	Leventer RJ, Scerri T, Marsh AP, et al. Hemispheric cortical dysplasia secondary to a mosaic somaticmutation in MTOR.Neurology, 2015, 84(20): 2029-2032.
29.	Poduri A.DEPDC5 does it all: shared genetics for diverse epilepsy syndromes.Ann Neurol, 2014, 75(5): 631-633.
30.	Picard F, Makrythanasis P, Navarro V, et al. DEPDC5 mutations in families presenting as auto-somal dominant nocturnal frontal lobe epilepsy.Neurology, 2014, 82(23): 2101-2106.
31.	Scheer 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.
32.	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.
33.	Nakashima M, Saitsu H, Takei N, et al. Somatic mutations in the MTOR gene cause focal cortical dysplasia type IIb.Ann Neurol, 2015, 78(3): 375-386.
34.	Lim JS, Kim WI, Kang HC, et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type Ⅱ leading to intractable epilepsy.Nat Med, 2015, 21(4): 395-400.
35.	Reiner O, Carrozzo R, Shen Y, et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats.Nature, 1993, 364(6439): 717-721.
36.	Bahi-Buisson N, Poirier K, Fourniol F, et al. The wide spectrum of tubulinopathies: what are the key features for the diagnosis.Brain, 2014, 137(Pt 6): 1676-1700.
37.	Tian G, Jaglin XH, Keays DA, et al. Disease associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway.Hum Mol Genet, 2010, 19(18): 3599-3613.
38.	Cederquist GY, Luchniak A, Tischfeld MA, et al. An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axondysinnervation.Hum Mol Genet, 2012, 21(26): 5484-5499.
39.	Tischfeld MA1, Baris HN, Wu C, et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.Cell, 2010, 140(1): 74-87.
40.	Hamilton EM, Wolf NI, van der Knaap MS.Reply: TUBB4A novel mutation reinforces the genotype-phenotype correlation of hypomyelination with atrophy of the basal ganglia and cerebellum.Brain, 2015, 138(Pt 2): e328.
41.	Romaniello R, Arrigoni F, Bassi MT, et al. Mutations in alpha-and beta-tubulin encoding genes: implications in brain malformations.Brain Dev, 2015, 37(3): 273-280.
42.	Tischfeld MA, Engle EC.Distinct alpha-and beta-tubulin isotypes are required for the positioning, dierentiation and survival of neurons: new support for the 'multi-tubulin' hypothesis.Biosci Rep, 2010, 30(5): 319-330.
43.	Esmaeeli NS, Madou MR, Sirajuddin M, et al. De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.Ann Clin Transl Neurol, 2015, 2(6): 623-635.
44.	Bardon-Cancho EJ, Munoz-Jimenez L, Vazquez-Lopez M, et al. Periventricular nodular heterotopia and dystonia due to an ARFGEF2 mutation.Pediatr Neurol, 2014, 51(3): 461-464.
45.	Lange M, Kasper B, Bohring A, et al. 47 patients with FLNA associated periventricular nodular heterotopia.Orphanet J Rare Dis, 2015, 10: 134.
46.	Carabalona A, Beguin S, Pallesi-Pocachard E, et al. A glial origin for periventricular nodular heterotopia caused by impaired expression of Filamin-A.Hum Mol Genet, 2012, 21(5): 1004-1017.
47.	Greenwood JS, Wang Y, Estrada RC, et al. Seizures, enhanced excitation, and increased vesicle number in Lis1 mutant mice.Ann Neurol, 2009, 66(5): 644-653.
48.	Hunt RF, Dinday MT, Hindle-Katel W, et al. LIS1 defciency promotes dysfunctional synaptic integration of granule cells generated in the developing and adult dentate gyrus.J Neurosci, 2012, 32(37): 12862-12875.
49.	Majewski J, BulmanDE, O'Driscoll M, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megal encephaly syndromes.Nat Genet, 2012, 44(8): 934-940.
50.	Santucci M, Meletti S, Berkovic SF, et al. Mutations in the mTOR pathway regulators NPRL2 and NPRL3 cause focal epilepsy.Ann Neurol, 2015, 79(1): 120-131.

1. Crino PB.mTOR signaling in epilepsy: insights from malformations of cortical development.Cold Spring Harb Perspect Med, 2015, 5(4): 422-442.
2. Tischfeld MA, Cederquist GY, Gupta ML Jr, et al. Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations.Curr Opin Genet Dev, 2011, 21(3): 286-294.
3. Han JM, Sahin M.TSC1/TSC2 signaling in the CNS.FEBS Lett, 2011, 585(7): 973-980.
4. Crino PB.Evolving neurobiology of tuberous sclerosis complex.Acta Neuropathol, 2013, 125(3): 317-332.
5. Riviere JB, Mirzaa GM, O'Roak BJ, et al. Finding of Rare Disease Genes (FORGE) Canada Consortium.Nat Genet, 2012, 44(8): 934-940.
6. Jansen LA, Mirzaa GM, Ishak GE, et al. PI3K/AKT pathway mutations cause a spectrum of brain malformations frommegalencephaly to focal cortical dysplasia.Brain, 2015, 138(Pt 6): 1613-1628.
7. Mirzaa GM, Riviere JB, Dobyns WB.Megalencephaly syndromes andactivating mutations in the PI3K-AKT pathway: MPPH and MCAP.Am JMed Genet C Semin Med Genet, 2013, 163(2): 122-130.
8. Roy A, Skibo J, Kalume F, et al. Mouse models of human PIK3CA-relatedbrain overgrowth have acutely treatable epilepsy.Elife, 2015, 4(3): piie12703.
9. Poduri A, Evrony GD, Cai X, et al. Somatic activationof AKT3 causes hemispheric developmental brain malformations.Neuron, 2012, 74(1): 41-48.
10. Baek ST, Copeland B, Yun EJ, et al. An AKT3-FOXG1-reelin network underlies defective migration in human focal malformations of cortical development.Nat Med, 2015, 21(12): 1445-1454.
11. Chang BS, Duzcan F, Kim S, et al. The role of RELN in lissencephaly and neuropsychiatric disease.Am J Med Genet B Neuropsychiatr Genet, 2007, 144(1): 58-63.
12. Moon UY, Park JY, Park R, et al. Impaired Reelin-Dab1 signaling contributes to neuronal mig-ration defcits of tuberous sclerosis complex.Cell Rep, 2015, 12(6): 965-978.
13. Eggers CM, Kline ER, Zhong D, et al. STE20-relatedkinase adaptor protein alpha (STRAD alpha) regulates cell polarityand invasion through PAK1 signaling in LKB1-null cells.J Biol Chem, 2012, 287(22): 18758-18768.
14. Orlova KA, Parker WE, Heuer GG, et al. STRADalpha defciency results in aberrant mTORC1 signaling during corticogenesis in humans and mice.J ClinInvest, 2010, 120(5): 1591-1602.
15. Parker WE, Orlova KA, Parker WH, et al. Rapamycin prevents seizures after depletion of ST-RADA in a rare neurodevelopmental disorder.Sci Transl Med, 2013, 182(5): 182ra53.
16. Pilarski R, Stephens JA, Noss R, et al. Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features.J Med Genet, 2011, 48(8): 505-512.
17. Ljungberg MC, Sunnen CN, Lugo JN, et al. Rapamycin suppresses seizures and neuronal hyp-ertrophy in a mousemodel of cortical dysplasia.Dis Model Mech, 2009, 2(7-8): 389-398.
18. Mester JL, Tilot AK, Rybicki LA, et al. Analysis of prevalence and degree of macrocephaly in patients with germline PTENmutations and of brain weight in Pten knock-in murine model.Eu-r JHum Genet, 2011, 19(7): 763-768.
19. Kwon CH, Zhu X, Zhang J, et al. mTOR is required for hypertrophyof Pten-defcient neuronal soma in vivo.Proc Natl Acad Sci USA, 2003, 100(22): 12923-12928.
20. Sunnen CN, Brewster AL, Lugo JN, et al. Inhibition of the mammalian target of rapamycin blocks epilepsy progression in NS-Pten conditional knockout mice.Epilepsia, 2011, 52(11): 2065-2075.
21. Bar-Peled L, Chantranupong L, Cherniack AD, et al. A Tumor suppressor complex with GAP activity for the RagGTPases that signal amino acid sufciency to mTORC1.Science, 2013, 340(6136): 1100-1106.
22. Alfaiz AA, Micale L, Mandriani B, et al. TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease.Hum Mutat, 2014, 35(4): 447-451.
23. 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, 2015, 79(1): 120-131.
24. Wei Y, Lilly MA.The TORC1 inhibitors Nprl2 and Nprl3 mediate anadaptive response to amino-acid starvation in Drosophila.Cell DeathDier, 2014, 21(9): 1460-1468.
25. Choi YJ, Di NA, Kramvis I, et al. Tuberous sclerosis complex proteins control axon formation.GenesDev, 2008, 22(18): 2485-2495.
26. Baulac S, Ishida S, Marsan E, et al. Familialfocal epilepsy with focal cortical dysplasia due to DEPDC5 mutations.Ann Neurol, 2015, 77(4): 675-683.
27. Chantranupong L, Wolfson RL, Orozco JM, et al. The Sestrins interactwith GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1.Cell Rep, 2014, 9(1): 1-8.
28. Leventer RJ, Scerri T, Marsh AP, et al. Hemispheric cortical dysplasia secondary to a mosaic somaticmutation in MTOR.Neurology, 2015, 84(20): 2029-2032.
29. Poduri A.DEPDC5 does it all: shared genetics for diverse epilepsy syndromes.Ann Neurol, 2014, 75(5): 631-633.
30. Picard F, Makrythanasis P, Navarro V, et al. DEPDC5 mutations in families presenting as auto-somal dominant nocturnal frontal lobe epilepsy.Neurology, 2014, 82(23): 2101-2106.
31. Scheer 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.
32. 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.
33. Nakashima M, Saitsu H, Takei N, et al. Somatic mutations in the MTOR gene cause focal cortical dysplasia type IIb.Ann Neurol, 2015, 78(3): 375-386.
34. Lim JS, Kim WI, Kang HC, et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type Ⅱ leading to intractable epilepsy.Nat Med, 2015, 21(4): 395-400.
35. Reiner O, Carrozzo R, Shen Y, et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats.Nature, 1993, 364(6439): 717-721.
36. Bahi-Buisson N, Poirier K, Fourniol F, et al. The wide spectrum of tubulinopathies: what are the key features for the diagnosis.Brain, 2014, 137(Pt 6): 1676-1700.
37. Tian G, Jaglin XH, Keays DA, et al. Disease associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway.Hum Mol Genet, 2010, 19(18): 3599-3613.
38. Cederquist GY, Luchniak A, Tischfeld MA, et al. An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axondysinnervation.Hum Mol Genet, 2012, 21(26): 5484-5499.
39. Tischfeld MA1, Baris HN, Wu C, et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance.Cell, 2010, 140(1): 74-87.
40. Hamilton EM, Wolf NI, van der Knaap MS.Reply: TUBB4A novel mutation reinforces the genotype-phenotype correlation of hypomyelination with atrophy of the basal ganglia and cerebellum.Brain, 2015, 138(Pt 2): e328.
41. Romaniello R, Arrigoni F, Bassi MT, et al. Mutations in alpha-and beta-tubulin encoding genes: implications in brain malformations.Brain Dev, 2015, 37(3): 273-280.
42. Tischfeld MA, Engle EC.Distinct alpha-and beta-tubulin isotypes are required for the positioning, dierentiation and survival of neurons: new support for the 'multi-tubulin' hypothesis.Biosci Rep, 2010, 30(5): 319-330.
43. Esmaeeli NS, Madou MR, Sirajuddin M, et al. De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.Ann Clin Transl Neurol, 2015, 2(6): 623-635.
44. Bardon-Cancho EJ, Munoz-Jimenez L, Vazquez-Lopez M, et al. Periventricular nodular heterotopia and dystonia due to an ARFGEF2 mutation.Pediatr Neurol, 2014, 51(3): 461-464.
45. Lange M, Kasper B, Bohring A, et al. 47 patients with FLNA associated periventricular nodular heterotopia.Orphanet J Rare Dis, 2015, 10: 134.
46. Carabalona A, Beguin S, Pallesi-Pocachard E, et al. A glial origin for periventricular nodular heterotopia caused by impaired expression of Filamin-A.Hum Mol Genet, 2012, 21(5): 1004-1017.
47. Greenwood JS, Wang Y, Estrada RC, et al. Seizures, enhanced excitation, and increased vesicle number in Lis1 mutant mice.Ann Neurol, 2009, 66(5): 644-653.
48. Hunt RF, Dinday MT, Hindle-Katel W, et al. LIS1 defciency promotes dysfunctional synaptic integration of granule cells generated in the developing and adult dentate gyrus.J Neurosci, 2012, 32(37): 12862-12875.
49. Majewski J, BulmanDE, O'Driscoll M, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megal encephaly syndromes.Nat Genet, 2012, 44(8): 934-940.
50. Santucci M, Meletti S, Berkovic SF, et al. Mutations in the mTOR pathway regulators NPRL2 and NPRL3 cause focal epilepsy.Ann Neurol, 2015, 79(1): 120-131.

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神經元移行障礙發病機制研究進展

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