title: De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing.
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.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tenpei
authors.initials: T
authors.lastname: Akita
authors.affiliation: Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Tohyama
authors.affiliation: Epilepsy Center, Schneider's Children Medical Center, Petah Tiqwa, Israel.
authors.forename: Hadassa
authors.initials: H
authors.lastname: Goldberg-Stern
authors.affiliation: Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Epilepsy Center, Schneider's Children Medical Center, Petah Tiqwa, Israel.
authors.forename: Roni
authors.initials: R
authors.lastname: Cohen
authors.affiliation: Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ohba
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D059472:Exome; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008564:Membrane Potentials / Q000235:genetics*; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D051669:Shab Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: C496988:KCNB1 protein, human; D051669:Shab Potassium Channels; D011188:Potassium