De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing.
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ABSTRACT:
SUBMITTER: Saitsu H
PROVIDER: S-EPMC4609934 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing.
Saitsu Hirotomo H Akita Tenpei T Tohyama Jun J Goldberg-Stern Hadassa H Kobayashi Yu Y Cohen Roni R Kato Mitsuhiro M Ohba Chihiro C Miyatake Satoko S Tsurusaki Yoshinori Y Nakashima Mitsuko M Miyake Noriko N Fukuda Atsuo A Matsumoto Naomichi N
Scientific reports 20151019
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 pat ...[more]
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Project description:ObjectiveNumerous studies have demonstrated increased load of de novo copy number variants or single nucleotide variants in individuals with neurodevelopmental disorders, including epileptic encephalopathies, intellectual disability, and autism.MethodsWe searched for de novo mutations in a family quartet with a sporadic case of epileptic encephalopathy with no known etiology to determine the underlying cause using high-coverage whole exome sequencing (WES) and lower-coverage whole genome sequencing. Mutations in additional patients were identified by WES. The effect of mutations on protein function was assessed in a heterologous expression system.ResultsWe identified a de novo missense mutation in KCNB1 that encodes the KV 2.1 voltage-gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on KV 2.1 function leading to a loss of ion selectivity and gain of a depolarizing inward cation conductance. Subsequently, we identified 2 additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that cause a similar pattern of KV 2.1 dysfunction.InterpretationOur genetic and functional evidence demonstrate that KCNB1 mutation can result in early onset epileptic encephalopathy. This expands the locus heterogeneity associated with epileptic encephalopathies and suggests that clinical WES may be useful for diagnosis of epileptic encephalopathies of unknown etiology.
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