Spectrum of K V 2.1 Dysfunction in KCNB1-Associated Neurodevelopmental Disorders.

Autor: Kang SK; Departments of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL., Vanoye CG; Departments of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL., Misra SN; Departments of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.; Departments of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL.; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL., Echevarria DM; Departments of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL., Calhoun JD; Departments of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL., O'Connor JB; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL., Fabre KL; Departments of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL., McKnight D; GeneDX, Gaithersburg, MD., Demmer L; Department of Pediatrics, Atrium Health's Levine Children's Hospital, Charlotte, NC., Goldenberg P; Medical Genetics, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA., Grote LE; Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, MO.; University of Missouri-Kansas City School of Medicine, Kansas City, MO., Thiffault I; University of Missouri-Kansas City School of Medicine, Kansas City, MO.; Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO.; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO., Saunders C; University of Missouri-Kansas City School of Medicine, Kansas City, MO.; Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO.; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO., Strauss KA; Clinic for Special Children, Strasburg, PA., Torkamani A; Scripps Translational Science Institute and Scripps Research Institute, La Jolla, CA., van der Smagt J; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., van Gassen K; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands., Carson RP; Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, TN., Diaz J; Rare Disease Institute, Children's National Medical Center, Washington, DC., Leon E; Rare Disease Institute, Children's National Medical Center, Washington, DC., Jacher JE; Division of Pediatric Genetics, Metabolism, and Genomic Medicine, University of Michigan, Ann Arbor, MI., Hannibal MC; Division of Pediatric Genetics, Metabolism, and Genomic Medicine, University of Michigan, Ann Arbor, MI., Litwin J; University of California, San Francisco Benioff Children's Hospital, San Francisco, CA., Friedman NR; Cleveland Clinic Children's, Cleveland, OH., Schreiber A; Cleveland Clinic Children's, Cleveland, OH., Lynch B; Department of Paediatric Neurology and Clinical Neurophysiology, Children's University Hospital, Dublin, Ireland., Poduri A; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA., Marsh ED; Division of Child Neurology, Children's Hospital of Philadelphia, Philadelphia, PA., Goldberg EM; Division of Child Neurology, Children's Hospital of Philadelphia, Philadelphia, PA., Millichap JJ; Departments of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL.; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.; Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL., George AL Jr; Departments of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL., Kearney JA; Departments of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL.
Jazyk: angličtina
Zdroj: Annals of neurology [Ann Neurol] 2019 Dec; Vol. 86 (6), pp. 899-912. Date of Electronic Publication: 2019 Oct 24.
DOI: 10.1002/ana.25607
Abstrakt: 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.
(© 2019 American Neurological Association.)
Databáze: MEDLINE
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