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A novel de novo KCNB1 variant altering channel characteristics in a patient with periventricular heterotopia, abnormal corpus callosum, and mild seizure outcome

Abstract

KCNB1 encodes the α-subunit of Kv2.1, the main contributor to neuronal delayed rectifier potassium currents. The subunit consists of six transmembrane α helices (S1–S6), comprising the voltage-sensing domain (S1–S4) and the pore domain (S5-P-S6). Heterozygous KCNB1 pathogenic variants are associated with developmental and epileptic encephalopathy. Here we report an individual who shows the milder phenotype compared to the previously reported cases, including delayed language development, mild intellectual disability, attention deficit hyperactivity disorder, late-onset epilepsy responsive to an antiepileptic drug, elevation of serum creatine kinase, and peripheral axonal neuropathy. On the other hand, his brain MRI showed characteristic findings including periventricular heterotopia, polymicrogyria, and abnormal corpus callosum. Exome sequencing identified a novel de novo KCNB1 variant c.574G>A, p.(Ala192Thr) located in the S1 segment of the voltage-sensing domain. Functional analysis using the whole-cell patch-clamp technique in Neuro2a cells showed that the Ala192Thr mutant reduces both activation and inactivation of the channel at membrane voltages in the range of −50 to −30 mV. Our case could expand the phenotypic spectrum of patients with KCNB1 variants, and suggested that variants located in the S1 segment might be associated with a milder outcome of seizures.

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Fig. 1: Brain MRI of the patient with the KCNB1 variant at 17 years of age.
Fig. 2: A KCNB1 variant in the patient and expression of Kv2.1 in N2A cells.
Fig. 3: Whole cell patch-clamp recordings in Kv2.1 mutant-transfected Neuro2a cells.

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Acknowledgements

We would like to thank the patients for participating in this work. This work was supported by Grants-in-Aid for Scientific Research (B) (JP20H03641), (C) (JP20K08236 and JP21K06766), and Grant-in-Aid for Challenging Research (Exploratory) (20K21570) from the Japan Society for the Promotion of Science, and the Takeda Science Foundation.

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TA and HS contributed to the conception and design of the study. TH, TA, KU, SM, MS, MK, and HS contributed to the acquisition and analysis of data. TH, TA, MN, MK, AF, and HS contributed to drafting the text and preparing the figure. All authors read and approved the final manuscript.

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Correspondence to Tenpei Akita or Hirotomo Saitsu.

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Hiraide, T., Akita, T., Uematsu, K. et al. A novel de novo KCNB1 variant altering channel characteristics in a patient with periventricular heterotopia, abnormal corpus callosum, and mild seizure outcome. J Hum Genet 68, 25–31 (2023). https://doi.org/10.1038/s10038-022-01090-5

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