Abstract
The voltage-gated Kv2.1 potassium channel encoded by KCNB1 produces the major delayed rectifier potassium current in pyramidal neurons. Recently, de novo heterozygous missense KCNB1 mutations have been identified in three patients with epileptic encephalopathy and a patient with neurodevelopmental disorder. However, the frequency of KCNB1 mutations in infantile epileptic patients and their effects on neuronal activity are yet unknown. We searched whole exome sequencing data of a total of 437 patients with infantile epilepsy, and found novel de novo heterozygous missense KCNB1 mutations in two patients showing psychomotor developmental delay and severe infantile generalized seizures with high-amplitude spike-and-wave electroencephalogram discharges. The mutation located in the channel voltage sensor (p.R306C) disrupted sensitivity and cooperativity of the sensor, while the mutation in the channel pore domain (p.G401R) selectively abolished endogenous Kv2 currents in transfected pyramidal neurons, indicating a dominant-negative effect. Both mutants inhibited repetitive neuronal firing through preventing production of deep interspike voltages. Thus KCNB1 mutations can be a rare genetic cause of infantile epilepsy, and insufficient firing of pyramidal neurons would disturb both development and stability of neuronal circuits, leading to the disease phenotypes.
Highlights
Kv2 includes Kv2.1 and Kv2.2, encoded by KCNB1 at 20q13.13 and KCNB2 at 8q13.3, respectively
De novo heterozygous KCNB1 mutations were reported in three patients with epileptic encephalopathy[16,17,18] and a patient with neurodevelopmental disorder[19]
The de novo mutation in KCNB1 (c.1201G> A (p.G401R)) was the most likely candidate because KCNB1 encodes Kv2.1, which is the major delayed rectifier Kv that regulates cortical pyramidal neuron excitability[14]. This assumption was later justified by recent reports of three patients with de novo KCNB1 mutations and epileptic encephalopathy[16,17,18]
Summary
Kv2 includes Kv2.1 and Kv2.2, encoded by KCNB1 at 20q13.13 and KCNB2 at 8q13.3, respectively. Kv2.1 expression can be modulated by neuronal activity via phosphorylation[15], which may control homeostatic changes in neuronal excitability[14]. De novo heterozygous KCNB1 mutations were reported in three patients with epileptic encephalopathy[16,17,18] and a patient with neurodevelopmental disorder[19]. Actual mutational effects on neuronal activity, which must be influenced by various properties of ion channels and other molecules, and frequency of KCNB1 mutations in epileptic patients, remains to be elucidated. We identified two patients with novel de novo heterozygous KCNB1 mutations (p.R306C and p.G401R) among 437 patients with infantile epilepsy. These mutations were located in the voltage-sensing and pore domains, respectively. Our study highlighted the importance of Kv2.1 for controlling neuronal activity in humans
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