Spectrum of KV2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders

Seok Kyu Kang, Carlos G. Vanoye, Sunita N. Misra, Dennis M. Echevarria, Jeffrey D. Calhoun, John B. O'Connor, Katarina L. Fabre, Dianalee McKnight, Laurie Demmer, Paula Goldenberg, Lauren E. Grote, Isabelle Thiffault, Carol Saunders, Kevin A. Strauss, Ali Torkamani, Jasper van der Smagt, Koen van Gassen, Robert P. Carson, Jullianne Diaz, Eyby LeonJoseph E. Jacher, Mark C. Hannibal, Jessica Litwin, Neil R. Friedman, Allison Schreiber, Bryan Lynch, Annapurna Poduri, Eric D. Marsh, Ethan M. Goldberg, John J. Millichap, Alfred L. George, Jennifer A. Kearney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


Objective: Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel KV2.1, 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 KV2.1 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 KV2.1. Quantification of protein expression also identified variants with reduced total KV2.1 expression or deficient cell-surface expression. Interpretation: Our study establishes a platform for rapid screening of KV2.1 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.

Original languageEnglish (US)
Pages (from-to)899-912
Number of pages14
JournalAnnals of neurology
Issue number6
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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