原钙粘蛋白与癫痫相关性研究进展_Journal of Epilepsy

Authors：

姜燕 ,  孔庆霞

济宁医学院附属医院神经内科（济宁 272029）;

Corresponding author：

孔庆霞, Email: kxdqy8@sohu.com

Keywords：

神经系统; 原钙粘蛋白; 癫痫; PCDH7; PCDH19

DOI：

10.7507/2096-0247.20210086

Video：

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神经系统在人体发育中正常发挥着作用与许多因素有关，最为重要的是相互联系的神经细胞，当其结构和功能发生变化时可能导致癫痫等神经疾病的发生。原钙粘蛋白（Protocadherins，PCDH）是钙粘蛋白家族（Cadherin Super family）中最大的亚类，包括 14 个同源蛋白和四个反义长链非编码 RNA。PCDH 蛋白质在钙存在的情况下介导神经组织中的细胞粘附，广泛参与了突触形成、神经元间连接及大脑发育等过程。作为神经发育过程中结构和功能的基本单位，神经元通过特殊的细胞间连接与其他神经细胞组成功能性神经回路，其细胞连接方式对于正常的神经功能的发挥起到重要作用。包括 PCDH 蛋白在内的细胞粘附分子是神经元之间识别、连接和相互作用的分子基础，促进了功能性神经元回路的形成。已有研究表明编码 PCDH 蛋白的基因发生变异时可导致癫痫的发生，但具体的发病机制和致病过程尚不清楚。本文主要围绕 PCDH 蛋白与癫痫的关系，结合同源基因进化、基因表达和基因功能等方面的解析，梳理了近年来 PCDH 蛋白参与癫痫发病机制的最新进展。

Citation： 姜燕, 孔庆霞. 原钙粘蛋白与癫痫相关性研究进展. Journal of Epilepsy, 2021, 7(6): 519-524. doi: 10.7507/2096-0247.20210086 Copy

1.	Perucca P, Scheffer IE, Kiley M. The management of epilepsy in children and adults. Med J Aust, 2018, 208(5): 226-233.
2.	Senn L, Cannazza G, Biagini G. Receptors and channels possibly mediating the effects of phytocannabinoids on seizures and epilepsy. Pharmaceuticals (Basel), 2020, 13(8): 174.
3.	Thijs RD, Surges R, O'brien TJ, et al. Epilepsy in adults. Lancet, 2019, 393(10172): 689-701.
4.	Molumby MJ, Anderson RM, Newbold DJ, et al. γ-Protocadherins interact with neuroligin-1 and negatively regulate dendritic spine morphogenesis. Cell Rep, 2017, 18(11): 2702-2714.
5.	Gul IS, Hulpiau P, Saeys Y, et al. Evolution and diversity of cadherins and catenins. Exp Cell Res, 2017, 358(1): 3-9.
6.	Guemez-gamboa A, Caglayan AO, Stanley V, et al. Loss of protocadherin-12 leads to diencephalic-mesencephalic junction dysplasia syndrome. Ann Neurol, 2018, 84(5): 638-647.
7.	Keeler AB, Molumby MJ, Weiner JA. Protocadherins branch out: multiple roles in dendrite development. Cell Adh Migr, 2015, 9(3): 214-226.
8.	Pederick DT, Homan CC, Jaehne EJ, et al. Pcdh19 loss-of-function increases neuronal migration in vitro but is dispensable for brain development in mice. Sci Rep, 2016, 6: 26765.
9.	Compagnmcci C, Petrini S, Higuraschi N, et al. Characterizing PCDH19 in human induced pluripotent stem cells (iPSCs) and iPSC-derived developing neurons: emerging role of a protein involved in controlling polarity during neurogenesis. Oncotarget, 2015, 6(29): 26804-26813.
10.	Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol, 2014, 13(9): 893-903.
11.	Emond MR, Biswas S, Morrow ML, et al. Proximity-dependent proteomics reveals extensive interactions of protocadherin-19 with regulators of rho GTPases and the microtubule cytoskeleton. Neuroscience, 2021, 452: 26-36.
12.	Asahina H, Masuba A, Hirano S, et al. Distribution of protocadherin 9 protein in the developing mouse nervous system. Neuroscience, 2012, 225: 88-104.
13.	Pancho A, Aerts T, Mitsogiannis MD, et al. Protocadherins at the crossroad of signaling pathways. Front Mol Neurosci, 2020, 13: 117.
14.	Depienne C, Leguern E. PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat, 2012, 33(4): 627-634.
15.	Yagi T. Clustered protocadherin family. Dev Growth Differ, 2008, 50: S131-S40.
16.	Yagi T. Genetic basis of neuronal individuality in the mammalian brain. J Neurogenet, 2013, 27(3): 97-105.
17.	Hayashi S, Takeichi M. Emerging roles of protocadherins: from self-avoidance to enhancement of motility. J Cell Sci, 2015, 128(8): 1455-1464.
18.	Light SEW, Jontes JD. δ-Protocadherins: organizers of neural circuit assembly. Semin Cell Dev Biol, 2017, 69: 83-90.
19.	Kim SY, Yasuda S, Tanaka H, et al. Non-clustered protocadherin. Cell Adh Migr, 2011, 5(2): 97-105.
20.	Trivisano M, Pietrafusa N, Terracciano A, et al. Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: a multicenter study. Epilepsia, 2018, 59(12): 2260-2271.
21.	Lal D, Ruppert AK, Trucks H, et al. Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. PLos Genet, 2015, 11(5): e1005226.
22.	Wang Y, Kerrisk Campbell M, Tom I, et al. PCDH7 interacts with GluN1 and regulates dendritic spine morphology and synaptic function. Sci Rep, 2020, 10(1): 10951.
23.	Merwick A, O'brien M, Delanty N. Complex single gene disorders and epilepsy. Epilepsia, 2012, 53(Suppl 4): 81-91.
24.	Niazi R, Fanning EA, Depienne C, et al. A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern. Hum Mutat, 2019, 40(3): 243-257.
25.	Serratto GM, Pizzi E, Murru L, et al. The epilepsy-related protein PCDH19 regulates tonic inhibition, GABAR kinetics, and the intrinsic excitability of hippocampal neurons. Mol Neurobiol, 2020, 57(12): 5336-5351.
26.	Camacho A, Simón R, Sanz R, et al. Cognitive and behavioral profile in females with epilepsy with PDCH19 mutation: two novel mutations and review of the literature. Epilepsy Behav, 2012, 24(1): 134-137.
27.	Gerosa L, Francolini M, Bassani S, et al. The role of protocadherin 19 (PCDH19) in neurodevelopment and in the pathophysiology of early infantile epileptic encephalopathy-9 (EIEE9). Dev Neurobiol, 2019, 79(1): 75-84.
28.	Homan CC, Pederson S, To TH, et al. PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 girls clustering epilepsy. Neurobiol Dis, 2018, 116: 106-119.
29.	Smith L, Singhal N, Elachkar CM, et al. PCDH19-related epilepsy is associated with a broad neurodevelopmental spectrum. Epilepsia, 2018, 59(3): 679-689.
30.	Bassani S, Cwetsch AW, Gerosa L, et al. The female epilepsy protein PCDH19 is a new GABAAR-binding partner that regulates GABAergic transmission as well as migration and morphological maturation of hippocampal neurons. Hum Mol Genet, 2018, 27(6): 1027-1038.
31.	Schaarschuch A, Hertel N. Expression profile of N-cadherin and protocadherin-19 in postnatal mouse limbic structures. J Comp Neurol, 2018, 526(4): 663-680.

1. Perucca P, Scheffer IE, Kiley M. The management of epilepsy in children and adults. Med J Aust, 2018, 208(5): 226-233.
2. Senn L, Cannazza G, Biagini G. Receptors and channels possibly mediating the effects of phytocannabinoids on seizures and epilepsy. Pharmaceuticals (Basel), 2020, 13(8): 174.
3. Thijs RD, Surges R, O'brien TJ, et al. Epilepsy in adults. Lancet, 2019, 393(10172): 689-701.
4. Molumby MJ, Anderson RM, Newbold DJ, et al. γ-Protocadherins interact with neuroligin-1 and negatively regulate dendritic spine morphogenesis. Cell Rep, 2017, 18(11): 2702-2714.
5. Gul IS, Hulpiau P, Saeys Y, et al. Evolution and diversity of cadherins and catenins. Exp Cell Res, 2017, 358(1): 3-9.
6. Guemez-gamboa A, Caglayan AO, Stanley V, et al. Loss of protocadherin-12 leads to diencephalic-mesencephalic junction dysplasia syndrome. Ann Neurol, 2018, 84(5): 638-647.
7. Keeler AB, Molumby MJ, Weiner JA. Protocadherins branch out: multiple roles in dendrite development. Cell Adh Migr, 2015, 9(3): 214-226.
8. Pederick DT, Homan CC, Jaehne EJ, et al. Pcdh19 loss-of-function increases neuronal migration in vitro but is dispensable for brain development in mice. Sci Rep, 2016, 6: 26765.
9. Compagnmcci C, Petrini S, Higuraschi N, et al. Characterizing PCDH19 in human induced pluripotent stem cells (iPSCs) and iPSC-derived developing neurons: emerging role of a protein involved in controlling polarity during neurogenesis. Oncotarget, 2015, 6(29): 26804-26813.
10. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol, 2014, 13(9): 893-903.
11. Emond MR, Biswas S, Morrow ML, et al. Proximity-dependent proteomics reveals extensive interactions of protocadherin-19 with regulators of rho GTPases and the microtubule cytoskeleton. Neuroscience, 2021, 452: 26-36.
12. Asahina H, Masuba A, Hirano S, et al. Distribution of protocadherin 9 protein in the developing mouse nervous system. Neuroscience, 2012, 225: 88-104.
13. Pancho A, Aerts T, Mitsogiannis MD, et al. Protocadherins at the crossroad of signaling pathways. Front Mol Neurosci, 2020, 13: 117.
14. Depienne C, Leguern E. PCDH19-related infantile epileptic encephalopathy: an unusual X-linked inheritance disorder. Hum Mutat, 2012, 33(4): 627-634.
15. Yagi T. Clustered protocadherin family. Dev Growth Differ, 2008, 50: S131-S40.
16. Yagi T. Genetic basis of neuronal individuality in the mammalian brain. J Neurogenet, 2013, 27(3): 97-105.
17. Hayashi S, Takeichi M. Emerging roles of protocadherins: from self-avoidance to enhancement of motility. J Cell Sci, 2015, 128(8): 1455-1464.
18. Light SEW, Jontes JD. δ-Protocadherins: organizers of neural circuit assembly. Semin Cell Dev Biol, 2017, 69: 83-90.
19. Kim SY, Yasuda S, Tanaka H, et al. Non-clustered protocadherin. Cell Adh Migr, 2011, 5(2): 97-105.
20. Trivisano M, Pietrafusa N, Terracciano A, et al. Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: a multicenter study. Epilepsia, 2018, 59(12): 2260-2271.
21. Lal D, Ruppert AK, Trucks H, et al. Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies. PLos Genet, 2015, 11(5): e1005226.
22. Wang Y, Kerrisk Campbell M, Tom I, et al. PCDH7 interacts with GluN1 and regulates dendritic spine morphology and synaptic function. Sci Rep, 2020, 10(1): 10951.
23. Merwick A, O'brien M, Delanty N. Complex single gene disorders and epilepsy. Epilepsia, 2012, 53(Suppl 4): 81-91.
24. Niazi R, Fanning EA, Depienne C, et al. A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern. Hum Mutat, 2019, 40(3): 243-257.
25. Serratto GM, Pizzi E, Murru L, et al. The epilepsy-related protein PCDH19 regulates tonic inhibition, GABAR kinetics, and the intrinsic excitability of hippocampal neurons. Mol Neurobiol, 2020, 57(12): 5336-5351.
26. Camacho A, Simón R, Sanz R, et al. Cognitive and behavioral profile in females with epilepsy with PDCH19 mutation: two novel mutations and review of the literature. Epilepsy Behav, 2012, 24(1): 134-137.
27. Gerosa L, Francolini M, Bassani S, et al. The role of protocadherin 19 (PCDH19) in neurodevelopment and in the pathophysiology of early infantile epileptic encephalopathy-9 (EIEE9). Dev Neurobiol, 2019, 79(1): 75-84.
28. Homan CC, Pederson S, To TH, et al. PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 girls clustering epilepsy. Neurobiol Dis, 2018, 116: 106-119.
29. Smith L, Singhal N, Elachkar CM, et al. PCDH19-related epilepsy is associated with a broad neurodevelopmental spectrum. Epilepsia, 2018, 59(3): 679-689.
30. Bassani S, Cwetsch AW, Gerosa L, et al. The female epilepsy protein PCDH19 is a new GABAAR-binding partner that regulates GABAergic transmission as well as migration and morphological maturation of hippocampal neurons. Hum Mol Genet, 2018, 27(6): 1027-1038.
31. Schaarschuch A, Hertel N. Expression profile of N-cadherin and protocadherin-19 in postnatal mouse limbic structures. J Comp Neurol, 2018, 526(4): 663-680.

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