De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing

Hirotomo Saitsu*, Tenpei Akita, Jun Tohyama, Hadassa Goldberg-Stern, Yu Kobayashi, Roni Cohen, Mitsuhiro Kato, Chihiro Ohba, Satoko Miyatake, Yoshinori Tsurusaki, Mitsuko Nakashima, Noriko Miyake, Atsuo Fukuda, Naomichi Matsumoto

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number15199
JournalScientific Reports
StatePublished - 19 Oct 2015
Externally publishedYes


FundersFunder number
Strategic Research Program for Brain Sciences11105137
challenging Exploratory Research26670505
Takeda Science Foundation
Japan Society for the Promotion of Science26670512, 25293052, 25293085, 26461549, 25293235, 15K19660
Ministry of Education, Culture, Sports, Science and Technology12024421
Japan Science and Technology Agency
Ministry of Health, Labour and Welfare13313587


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