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Spectrum of K V 2.1 Dysfunction in KCNB1 ‐Associated Neurodevelopmental Disorders
Author(s) -
Kang Seok Kyu,
Vanoye Carlos G.,
Misra Sunita N.,
Echevarria Dennis M.,
Calhoun Jeffrey D.,
O'Connor John B.,
Fabre Katarina L.,
McKnight Dianalee,
Demmer Laurie,
Goldenberg Paula,
Grote Lauren E.,
Thiffault Isabelle,
Saunders Carol,
Strauss Kevin A.,
Torkamani Ali,
der Smagt Jasper,
Gassen Koen,
Carson Robert P.,
Diaz Jullianne,
Leon Eyby,
Jacher Joseph E.,
Hannibal Mark C.,
Litwin Jessica,
Friedman Neil R.,
Schreiber Allison,
Lynch Bryan,
Poduri Annapurna,
Marsh Eric D.,
Goldberg Ethan M.,
Millichap John J.,
George Alfred L.,
Kearney Jennifer A.
Publication year - 2019
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25607
Subject(s) - phenotype , heterologous expression , biology , hek 293 cells , potassium channel , loss function , genetics , gene , microbiology and biotechnology , biophysics , recombinant dna
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