Identifying mutation hotspots reveals pathogenetic mechanisms of KCNQ2 epileptic encephalopathy

被引:0
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作者
Jiaren Zhang
Eung Chang Kim
Congcong Chen
Erik Procko
Shashank Pant
Kin Lam
Jaimin Patel
Rebecca Choi
Mary Hong
Dhruv Joshi
Eric Bolton
Emad Tajkhorshid
Hee Jung Chung
机构
[1] Department of Molecular and Integrative Physiology,
[2] University of Illinois at Urbana-Champaign,undefined
[3] Department of Statistics,undefined
[4] University of Illinois at Urbana-Champaign,undefined
[5] Department of Biochemistry,undefined
[6] University of Illinois at Urbana-Champaign,undefined
[7] Neuroscience Program,undefined
[8] University of Illinois at Urbana-Champaign,undefined
[9] NIH Center for Macromolecular Modeling and Bioinformatics,undefined
[10] Beckman Institute for Advanced Science and Technology,undefined
[11] University of Illinois at Urbana-Champaign,undefined
[12] Center for Biophysics and Quantitative Biology,undefined
[13] University of Illinois at Urbana-Champaign,undefined
[14] Department of Physics,undefined
[15] University of Illinois at Urbana-Champaign,undefined
来源
Scientific Reports | / 10卷
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摘要
Kv7 channels are enriched at the axonal plasma membrane where their voltage-dependent potassium currents suppress neuronal excitability. Mutations in Kv7.2 and Kv7.3 subunits cause epileptic encephalopathy (EE), yet the underlying pathogenetic mechanism is unclear. Here, we used novel statistical algorithms and structural modeling to identify EE mutation hotspots in key functional domains of Kv7.2 including voltage sensing S4, the pore loop and S6 in the pore domain, and intracellular calmodulin-binding helix B and helix B-C linker. Characterization of selected EE mutations from these hotspots revealed that L203P at S4 induces a large depolarizing shift in voltage dependence of Kv7.2 channels and L268F at the pore decreases their current densities. While L268F severely reduces expression of heteromeric channels in hippocampal neurons without affecting internalization, K552T and R553L mutations at distal helix B decrease calmodulin-binding and axonal enrichment. Importantly, L268F, K552T, and R553L mutations disrupt current potentiation by increasing phosphatidylinositol 4,5-bisphosphate (PIP2), and our molecular dynamics simulation suggests PIP2 interaction with these residues. Together, these findings demonstrate that each EE variant causes a unique combination of defects in Kv7 channel function and neuronal expression, and suggest a critical need for both prediction algorithms and experimental interrogations to understand pathophysiology of Kv7-associated EE.
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