Deficiency of SCAMP5 leads to pediatric epilepsy and dysregulation of neurotransmitter release in the brain.,Human Genetics

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Deficiency of SCAMP5 leads to pediatric epilepsy and dysregulation of neurotransmitter release in the brain.
Human Genetics ( IF 3.8 ) Pub Date : 2020-02-04 , DOI: 10.1007/s00439-020-02123-9
Dazhi Zhang ₁ , Chao Yuan _{1,

2} , Mengxue Liu ₃ , Xiaopei Zhou ₁ , Shunnan Ge ₄ , Xuelian Wang ₄ , Geng Luo ₁ , Meiqi Hou ₁ , Zhenxing Liu ₁ , Qing K Wang _{1,

5} , Xu Wang _{6,

7} , Haohong Li _{6,

7} , Yang Tan ₁ , Weimin Jia ₁ , Jiarui Wang ₁ , Yanling Wu ₁ , Ali Wang ₁ , Xiaofei Yang ₃ , Xianqin Zhang ₁

Affiliation

Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, 430074, China.
Hubei Key Laboratory for Kidney Disease Pathogenesis and Intervention, Huangshi Cental Hospital of Edong Healthcare Group, Hubei Polytechnic University School of Medicine, Huangshi, China.
Key Laboratory of Cognitive Science, Key Laboratory of Medical Information Analysis and Tumor Diagnosis and Treatment, Laboratory of Membrane Ion Channels and Medicine, College of Biomedical Engineering, South-Central University for Nationalities, Wuhan, 430074, China.
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China.
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan, 430074, China.
MoE Key Laboratory for Biomedical Photonics, Collaborative Innovation Center for Biomedical Engineering, School of Engineering Sciences, Huazhong University of Science and Technology, Wuhan, 430074, China.

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.

更新日期：2020-03-26

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