Dataset Information

Spectrum of K_V 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.

ABSTRACT: OBJECTIVE:Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel K_V 2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression. METHODS:We evaluated a series of 17 KCNB1 variants associated with DEE or other neurodevelopmental disorders (NDDs) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant K_V 2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry. RESULTS:Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage dependence of activation and/or inactivation, as homotetramers or when coexpressed with wild-type K_V 2.1. Quantification of protein expression also identified variants with reduced total K_V 2.1 expression or deficient cell-surface expression. INTERPRETATION:Our study establishes a platform for rapid screening of K_V 2.1 functional defects caused by KCNB1 variants associated with DEE and other NDDs. This will aid in establishing KCNB1 variant pathogenicity and the mechanism of dysfunction, which will enable targeted strategies for therapeutic intervention based on molecular phenotype. ANN NEUROL 2019;86:899-912.

SUBMITTER: Kang SK

PROVIDER: S-EPMC7025436 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

Spectrum of K<sub>V</sub> 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.

Kang Seok Kyu SK Vanoye Carlos G CG Misra Sunita N SN Echevarria Dennis M DM Calhoun Jeffrey D JD O'Connor John B JB Fabre Katarina L KL McKnight Dianalee D Demmer Laurie L Goldenberg Paula P Grote Lauren E LE Thiffault Isabelle I Saunders Carol C Strauss Kevin A KA Torkamani Ali A van der Smagt Jasper J van Gassen Koen K Carson Robert P RP Diaz Jullianne J Leon Eyby E Jacher Joseph E JE Hannibal Mark C MC Litwin Jessica J Friedman Neil R NR Schreiber Allison A Lynch Bryan B Poduri Annapurna A Marsh Eric D ED Goldberg Ethan M EM Millichap John J JJ George Alfred L AL Kearney Jennifer A JA

Annals of neurology 20191024 6

<h4>Objective</h4>Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel K<sub>V</sub> 2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression.<h4>Methods</h4>We evaluated a series of 17 KCNB1 variants associat ...[more]

PMID: 31600826

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Project description:Importance:Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients. Objectives:To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations. Design, Setting, and Participants:This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project. Main Outcomes and Measures:The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one. Results:Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region. Conclusions and Relevance:De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.

Dataset Information

Spectrum of K_V 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.

Publications

Spectrum of K<sub>V</sub> 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.

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Dataset Information

Spectrum of KV 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.

Publications

Spectrum of K<sub>V</sub> 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Spectrum of K_V 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.