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, and Hee Jung Chung.
Identifying mutation hotspots reveals pathogenetic mechanisms of
KCNQ2 epileptic encephalopathy.
Scientific Reports, 10:4756, 2020.
(PMC: PMC7075958)
ZHAN2020-ET
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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