Synapsin Gene Mutations in Idiopathic Generalized Epilepsy Patients in Pakistan

• Mehwish Riaz

  Cell & Molecular Biology Lab, Institute of Zoology, University of the Punjab, Q-A- Campus, Lahore, 54590, Pakistan

  Author

• Nadeem Sheikh

  Cell & Molecular Biology Lab, Institute of Zoology, University of the Punjab, Q-A- Campus, Lahore, 54590, Pakistan

  Author

  https://orcid.org/0000-0001-9503-9538

• Tayyaba Saleem

  Department of Neurology, University Medical Center, Georg-August-Universitäts, Robert-Koch-straße 40, 37075, Göttingen, Germany

  Author

  https://orcid.org/0000-0003-4920-1463

• Muddasir Hassan Abbasi

  Guangzhou Women and Children's Medical Center, Guangzhou Medical University-China

  Author

  https://orcid.org/0000-0001-7856-7013

Background: Epilepsy is a heterogeneous, multifactorial disease in which genetics plays an important role. The synapsin (SYN2) gene has been considered one of the important epilepsy-associated candidate genes that plays an important role in epileptogenesis. Although various studies conducted in different countries have evaluated the association between the onset of epilepsy and the presence of the SYN2 rs3773364 variant, such an association has not yet been evaluated in Pakistan. Therefore, the aim of this study was to determine the genetic association of the SYN2 rs3773364 variant with the onset of epilepsy in the population of Pakistan.

Materials and Methods: Blood samples of 150 epilepsy patients and 150 healthy controls who were recruited in our previous research on the genetic association of GABA receptor gene polymorphisms with epilepsy were employed for the isolation of genomic DNA for further analysis through PCR and DNA sequencing method.

Results: Both homozygous and heterozygous mutations were detected in epileptic patients. Single-site analysis showed significant differences in the genotypic and allelic frequencies of SNP rs3773364 in both epileptic patients and controls, with a p-value of 0.0003.

Conclusion: The SNP rs3773364 of SYN2 significantly contributes to the epilepsy onset in Pakistan. The outcomes suggested that the SYN2 gene might play a critical role in the progression of epilepsy among patients in Pakistan.

Bonanomi, D., Menegon, A., Miccio, A., Ferrari, G., Corradi, A., Kao, H. T., Benfenati, F., & Valtorta, F. (2005). Phosphorylation of synapsin I by cAMP-dependent protein kinase controls synaptic vesicle dynamics in developing neurons. Journal of Neuroscience, 25(32). https://doi.org/10.1523/JNEUROSCI.1573-05.2005

Cavalleri, G. L., Weale, M. E., Shianna, K. V., Singh, R.,Lynch, J. M., Grinton, B., Szoeke, C., Murphy, K., Kinirons, P., O’Rourke, D., Ge, D., Depondt, C., Claeys, K. G., Pandolfo, M., Gumbs, C., Walley, N., McNamara, J., Mulley, J. C., Linney, K. N., … Goldstein, D. B. (2007). Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study. Lancet Neurology, 6(11). https://doi.org/10.1016/S1474-4422(07)70247-8

Cesca, F., Baldelli, P., Valtorta, F., & Benfenati, F. (2010). The synapsins: Key actors of synapse function and plasticity. Progress in Neurobiology, 91(4). https://doi.org/10.1016/j.pneurobio.2010.04.006

Chesnokova, E., Bal, N., Alhalabi, G., & Balaban, P. (2025). Regulatory Elements for Gene Therapy of Epilepsy. Cells, 14(3). https://doi.org/10.3390/cells14030236

Chiappalone, M., Casagrande, S., Tedesco, M., Valtorta, F., Baldelli, P., Martinoia, S., & Benfenati, F. (2009). Opposite changes in glutamatergic and GABAergic transmission underlie the diffuse hyperexcitability of synapsin i-deficient cortical networks. Cerebral Cortex, 19(6). https://doi.org/10.1093/cercor/bhn182

Etholm, L., & Heggelund, P. (2009). Seizure elements and seizure element transitions during tonic-clonic seizure activity in the synapsin I/II double knockout mouse: A neuroethological description. Epilepsy and Behavior, 14(4). https://doi.org/10.1016/j.yebeh.2009.02.021

Farisello, P., Boido, D., Nieus, T., Medrihan, L., Cesca, F., Valtorta, F., Baldelli, P., & Benfenati, F. (2013). Synaptic and extrasynaptic origin of the excitation/inhibition imbalance in the hippocampus of synapsin I/II/III knockout mice. Cerebral Cortex, 23(3). https://doi.org/10.1093/cercor/bhs041

Fassio, A., Patry, L., Congia, S., Onofri, F., Piton, A., Gauthier, J., Pozzi, D., Messa, M., Defranchi, E., Fadda, M., Corradi, A., Baldelli, P., Lapointe, L., St-Onge, J., Meloche, C., Mottron, L., Valtorta, F., Nguyen, D. K., Rouleau, G. A., … Cossette, P. (2011). SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function. Human Molecular Genetics, 20(12). https://doi.org/10.1093/hmg/ddr122

Feng, J., Chi, P., Blanpied, T. A., Xu, Y., Magarinos, A. M., Ferreira, A., Takahashi, R. H., Kao, H. T., McEwen, B. S., Ryan, T. A., Augustine, G. J., & Greengard, P. (2002). Regulation of Neurotransmitter Release by Synapsin III. Journal of Neuroscience, 22(11). https://doi.org/10.1523/jneurosci.22-11-04372.2002

Forte, N., Nicois, A., Marfella, B., Mavaro, I., D’Angelo, L., Piscitelli, F., Scandurra, A., De Girolamo, P., Baldelli, P., Benfenati, F., Di Marzo, V., & Cristino, L. (2024). Early endocannabinoid-mediated depolarization-induced suppression of excitation delays the appearance of the epileptic phenotype in synapsin II knockout mice. Cellular and Molecular Life Sciences, 81(1). https://doi.org/10.1007/s00018-023-05029-7

Fukata, Y., & Fukata, M. (2017). Epilepsy and synaptic proteins. Current Opinion in Neurobiology, 45. https://doi.org/10.1016/j.conb.2017.02.001

Garcia, C. C., Blair, H. J., Seager, M., Coulthard, A., Tennant, S., Buddles, M., Curtis, A., & Goodship, J. A. (2004). Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy. Journal of Medical Genetics, 41(3). https://doi.org/10.1136/jmg.2003.013680

Hameedi, A. J., & Saud, A. M. (2021). Association of the Intronic Polymorphism rs3773364 A>G in Synapsin-2 Gene with Epilepsy Patients in Iraq. Iraqi Journal of Science, 62(7). https://doi.org/10.24996/ijs.2021.62.7.6

Hilfiker, S., Benfenati, F., Doussau, F., Nairn, A. C., Czernik, A. J., Augustine, G. J., & Greengard, P. (2005). Structural domains involved in the regulation of transmitter release by synapsins. Journal of Neuroscience, 25(10). https://doi.org/10.1523/JNEUROSCI.4278-04.2005

Kielland, A., Erisir, A., Walaas, S. I., & Heggelund, P. (2006). Synapsin utilization differs among functional classes of synapses on thalamocortical cells. Journal of Neuroscience, 26(21). https://doi.org/10.1523/JNEUROSCI.4631-05.2006

Lakhan, R., Kalita, J., Misra, U. K., Kumari, R., & Mittal, B. (2010). Association of intronic polymorphism rs3773364 A>G in synapsin-2 gene with idiopathic epilepsy. Synapse, 64(5). https://doi.org/10.1002/syn.20740

Messa, M., Congia, S., Defranchi, E., Valtorta, F., Fassio, A., Onofri, F., & Benfenati, F. (2010). Tyrosine phosphorylation of synapsin I by Src regulates synaptic-vesicle trafficking. Journal of Cell Science, 123(13). https://doi.org/10.1242/jcs.068445

Mirza, F. J., & Zahid, S. (2018). The Role of Synapsins in Neurological Disorders. Neuroscience Bulletin, 34(2).. https://doi.org/10.1007/s12264-017-0201-7

Molinaro, L., Hui, P., Tan, M., & Mishra, R. K. (2015). Role of presynaptic phosphoprotein synapsin II in schizophrenia. World Journal of Psychiatry, 5(3). https://doi.org/10.5498/wjp.v5.i3.260

Muhigwa, A., Preux, P. M., Gérard, D., Marin, B., Boumediène, F., Ntamwira, C., & Tsai, C. H. (2020). Comorbidities of epilepsy in low and middle-income countries: systematic review and meta-analysis. Scientific Reports, 10(1). https://doi.org/10.1038/s41598-020-65768-6

Nadeem, M. S., Ahmad, H., Mohammed, K., Muhammad, K., Ullah, I., Baothman, O. A. S., Ali, N., Anwar, F., Zamzami, M. A., & Shakoori, A. R. (2018). Identification of variants in the mitochondrial lysine-tRNA (MT-TK) gene in myoclonic epilepsy—pathogenicity evaluation and structural characterization by in silico approach. Journal of Cellular Biochemistry, 119(7). https://doi.org/10.1002/jcb.26857

Porton, B., Wetsel, W. C., & Kao, H. T. (2011). Synapsin III: Role in neuronal plasticity and disease. Seminars in Cell and Developmental Biology, 22(4). https://doi.org/10.1016/j.semcdb.2011.07.007

Prasad, D. K. V., Shaheen, U., Satyanarayana, U., Prabha, T. S., Jyothy, A., & Munshi, A. (2014). Association of GABRA6 1519 T>C (rs3219151) and Synapsin II (rs37733634) gene polymorphisms with the development of idiopathic generalized epilepsy. Epilepsy Research, 108(8). https://doi.org/10.1016/j.eplepsyres.2014.07.001

Qian, X., Ding, J. Q., Zhao, X., Sheng, X. W., Wang, Z. R., Yang, Q. X., Zheng, J. J., Zhong, J. G., Zhang, T. Y., He, S. Q., Ji, W. D., Li, W., & Zhang, M. (2022). Proteomic Analysis Reveals the Vital Role of Synaptic Plasticity in the Pathogenesis of Temporal Lobe Epilepsy. Neural Plasticity, 2022. https://doi.org/10.1155/2022/8511066

Riaz, M., Abbasi, M. H., Sheikh, N., Saleem, T., & Virk, A. O. (2021). GABRA1 and GABRA6 gene mutations in idiopathic generalized epilepsy patients. Seizure, 93. https://doi.org/10.1016/j.seizure.2021.10.013

Saviouk, V., Moreau, M. P., Tereshchenko, I. V., & Brzustowicz, L. M. (2007). Association of synapsin 2 with schizophrenia in families of Northern European ancestry. Schizophrenia Research, 96(1–3), 100-111. https://doi.org/10.1016/j.schres.2007.07.031

Schwark, R., Andrade, R., & Bykhovskaia, M. (2022). Synapsin II Directly Suppresses Epileptic Seizures In Vivo. Brain Sciences, 12(3). https://doi.org/10.3390/brainsci12030325

Sharma, M., Pamidi, S. C., Divi, P. K., Mohapatra, S., George, B., Sneha, K. P., Kreutzmann, J. C., & Annamneedi, A. (2025). Genetic crosstalk of autism spectrum disorders and epilepsy: an insight into the presynapse. Frontiers in Neurology, 16. https://doi.org/10.3389/fneur.2025.1677134

Song, S. H., & Augustine, G. J. (2015). Synapsin isoforms and synaptic vesicle trafficking. Molecules and Cells, 38(11). https://doi.org/10.14348/molcells.2015.0233

Tanveer, M., Ahmed, A., Iqbal, M., Aslam, F., Saqlain, M., Ur Rehman, I., & Khurshid Hashmi, F. (2022). Excessive Daytime Sleepiness and Sleep Quality and their Impact on Health-Related Quality of Life in People with Epilepsy: A study from Pakistan. Epilepsy and Behavior, 128. https://doi.org/10.1016/j.yebeh.2022.108565

Turner, T. J., Zourray, C., Schorge, S., & Lignani, G. (2021). Recent advances in gene therapy for neurodevelopmental disorders with epilepsy. Journal of Neurochemistry, 157(2). https://doi.org/10.1111/jnc.15168

Vannini, E., Restani, L., Dilillo, M., McDonnell, L. A., Caleo, M., & Marra, V. (2020). Synaptic Vesicles Dynamics in Neocortical Epilepsy. Frontiers in Cellular Neuroscience, 14. https://doi.org/10.3389/fncel.2020.606142

Wang, J., Lin, Z. J., Liu, L., Xu, H. Q., Shi, Y. W., Yi, Y. H., He, N., & Liao, W. P. (2017). Epilepsy-associated genes. Seizure, 44. https://doi.org/10.1016/j.seizure.2016.11.030

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