Characterization of a KCNB1 variant associated with autism, intellectual disability, and epilepsy. (December 2017)

• Record Type: Journal Article
• Authors: Calhoun, Jeffrey D.; Vanoye, Carlos G.; Kok, Fernando; George, Alfred L.; Kearney, Jennifer A.
• Is Part Of: Neurology. Volume 3:Number 6(2017)
• Publication Date: 2017-12
• Subjects: Neurogenetics -- Periodicals; 616.80442
• DOI: 10.1212/NXG.0000000000000198
• Languages: English
• ISSNs: 2376-7839

Abstract

Abstract : Objective: To perform functional characterization of a potentially pathogenic KCNB1 variant identified by clinical exome sequencing of a proband with a neurodevelopmental disorder that included epilepsy and centrotemporal spikes on EEG. Methods: Whole-exome sequencing identified the KCNB1 variant c.595A>T (p.Ile199Phe). Biochemical and electrophysiologic experiments were performed to determine whether this variant affected protein expression, trafficking, and channel functional properties. Results: Biochemical characterization of the variant suggested normal protein expression and trafficking. Functional characterization revealed biophysical channel defects in assembled homotetrameric and heterotetrameric channels. Conclusions: The identification of the KCNB1 variant c.595A>T (p.Ile199Phe) in a neurodevelopmental disorder that included epilepsy with centrotemporal spikes expands the phenotypic spectrum of epilepsies associated with KCNB1 variants. The KCNB1-I199F variant exhibited partial loss of function relative to the wild-type channel. This defect is arguably less severe than previously reported KCNB1 variants, suggesting the possibility that the degree of KCNB1 protein dysfunction may influence disease severity.