Abstract
Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson’s disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.
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Acknowledgements
We would like thank the family members for their enthusiastic participation in this study. This work is supported by the National Natural Science Foundation of China grants (81000079, 81170165 and 81870959 to X.Z.) and supported by Program for HUST Academic Frontier Youth Team.
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XQZ leaded and supervised the work and designed the experiments, DZ, XQZ, ML and XY wrote the manuscript. DZ, CY, ML, XPZ, GL, MH, ZL, XW, YT, WJ, JW, YW, AW performed experiments. XY designed the patch-clamp experiments. SG and XW took clinical care of the patients and QKW and HL provided advice.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee on human subject research at Huazhong University of Science and Technology (2014IECs066) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from the participants. All experiments involving animals were approved by the Ethics Committee on Animal Research of Huazhong University of Science and Technology (S672).
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Zhang, D., Yuan, C., Liu, M. et al. Deficiency of SCAMP5 leads to pediatric epilepsy and dysregulation of neurotransmitter release in the brain. Hum Genet 139, 545–555 (2020). https://doi.org/10.1007/s00439-020-02123-9
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DOI: https://doi.org/10.1007/s00439-020-02123-9