The Function of Potassium Channel in KCNQ2 G271V Mutants of Benign Familial Neonatal Convulsions

HUI Zhi-yan, ZHANG Xu, SUN Hong-mei. et al

Abstract

To determine the function of potassium channel in KCNQ2 G271V mutants of benign familial neonatal convulsions. Methods HEK293 cells were transfected with pcDNA3-WT-KCNQ2 and / or pcDNA3-G271V-KCNQ2 and pcDNA3-WT-KCNQ3. The potassium channel function of G271V mutants was assessed using the whole cell patch clamp technique. Results G271V mutants did not show currents in the transfected HEK cells, inducing large depolarizing shift of the conductance voltage relationship and slowing down the current activation kinetics. The required current density was (2.47±0.41) pA/pF (n=12) for the expression of G271V, and whereas (20.53±2.51) pA/pF (n=10,Pn=15) and Kv7.2/G271V/Kv7.3 (42.71±6.27) pA/pF (n=10), G271V/Kv7.3 induced almost no current (3.74±0.76) pA/pF (n=10，P<0.05), resulting in about 50% reduction of currents in Kv7.2/G271V/Kv7.3 in the heteromultimeric condition. Conclusion The G271V channel fails to open potassium currents in response to depolarization, indicating a more severe functional defect of the Kv7 potassium channel.

 

Keywords: Epilepsy KCNQ2 Kv7.2, Voltage-gated potassium channel, Patch-clamp electrophysiology 

 

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MALJEVIC S, WUTTKE TV, SEEBOHM G, et al. KV7 channelopathies. Pflugers Arch,2010,460(2) :277-288.

COOPER EC, JAN LY. M-channels: neurological diseases, neuromodulation, and drug development. Arch Neurol,2003, 60(4);496-500.

SINGH NA, OTTO JF, DAHLE EJ, et al. Mouse models of human KCNQ2, and KCNQ3, mutations for benign familial neonatal convulsions show seizures and neuronal plasticity without synaptic reorganization. J Physiol, 2008, 586(14):3405-3423.

MALJEVIC S, LERCHE H. Potassium channel genes and benign familial neonatal epilepsy. Prog Brain Res. 2014 .213 : 17-53[2018-01-05]. https://doi. org/10. 1016/B978-0-444- 63326-2. 00002-8.

WECKHUYSEN S, MANDELSTAM S. SULS A. et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Arch Neurol.2012,71 ( 1): 15-25.

WECKHUYSEN S. IVANOVIC V. HENDRICKX R. et al. Extending the KCNQ2 encephalopathy spectrum; clinical and neuroimaging findings in 17 patients. Neurology, 2013, 81 (19); 1697-703.

MALJEVIC S, NAROS G, YALQIN O, et al. Temperature and pharmacological rescue of a folding-defective, dominant- negative KV 7. 2 mutation associated with neonatal seizures. Hum Mutat, 2011, 32 ( 10 ); E2283-E2293 [2018-01-05]. https;//doi. org/10. 1002/humu. 21554.

SCHROEDER BC, KUBISCH C, STEIN V, et al. Moderate loss of function of cyclic-AMP-modulated KCNQ2/ KCNQ3 K~ channels causes epilepsy. Nature, 1998,396 (6712):687-690.

SOLDOVIERl MV, CASTALDO P, IODICE L, et al. Decreased subunit stability as a novel mechanism for potassium current impairment by a KCNQ2 С terminus mutation causing benign familial neonatal convulsions. J Biol Chem, 2006,281(1): 418-428.

OR HAN G, BOCK M, SCHEPERS D, et al. Dominant- negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol,2014,75(3) ;382-394.

SOLDOVIERl MV, MICELI F, BELLINI G, et al. Correlating the clinical and genetic features of benign familial neonatal seizures (BFNS) with the functional consequences of underlying mutations. Channels,2007,1(4) ;228-233.

CHARLIERC, SINGH NA, RYAN SG, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet,1998, 18( 1) ;53-55. GUISCARD S. MICHAEL P, SANGUINETTI MC. Pharmacological activation of normal and arrhythmia- associated mutant KCNQ1 potassium channels. Circ Res, 2003,93(10):9il-947.

SUGIURA Y. NAKATSU F, HIROYASU K, et al. Lack of potassium current in W309R mutant KCNQ3 channel causing benign familial neonatal convulsions ( BFNC ). Epilepsy Res,2009,84(l):82-85.

DEDEKK, KUNATH B, KANANURA C, et al. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 К “ channel. Proc Natl Acad Sci U S A,2001,98(21): 12272-12277.

WUTTKE TV, JURKAT-ROTT K, PAULUS W. et al. Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations. Neurology ,2007 ,69(22) :2045-2053.


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