De novo KCNB1 mutations in epileptic encephalopathy.

Autor: Torkamani A; The Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, San Diego, CA 92037., Bersell K; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA., Jorge BS; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37232, USA., Bjork RL Jr; Pediatrics, Scripps Health, San Diego, CA 92037, USA.; Sea Breeze Pediatrics, APC, San Diego, CA., Friedman JR; Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA., Bloss CS; The Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute, San Diego, CA 92037., Cohen J; Kennedy Krieger Institute, Baltimore, MD 21205., Gupta S; Kennedy Krieger Institute, Baltimore, MD 21205.; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Naidu S; Kennedy Krieger Institute, Baltimore, MD 21205.; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287., Vanoye CG; Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611., George AL Jr; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.; Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611., Kearney JA; Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA.; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
Jazyk: angličtina
Zdroj: Annals of neurology [Ann Neurol] 2014 Oct; Vol. 76 (4), pp. 529-540. Date of Electronic Publication: 2014 Sep 19.
DOI: 10.1002/ana.24263
Abstrakt: Objective: Numerous studies have demonstrated increased load of de novo copy number variants or single nucleotide variants in individuals with neurodevelopmental disorders, including epileptic encephalopathies, intellectual disability, and autism.
Methods: We searched for de novo mutations in a family quartet with a sporadic case of epileptic encephalopathy with no known etiology to determine the underlying cause using high-coverage whole exome sequencing (WES) and lower-coverage whole genome sequencing. Mutations in additional patients were identified by WES. The effect of mutations on protein function was assessed in a heterologous expression system.
Results: We identified a de novo missense mutation in KCNB1 that encodes the KV 2.1 voltage-gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on KV 2.1 function leading to a loss of ion selectivity and gain of a depolarizing inward cation conductance. Subsequently, we identified 2 additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that cause a similar pattern of KV 2.1 dysfunction.
Interpretation: Our genetic and functional evidence demonstrate that KCNB1 mutation can result in early onset epileptic encephalopathy. This expands the locus heterogeneity associated with epileptic encephalopathies and suggests that clinical WES may be useful for diagnosis of epileptic encephalopathies of unknown etiology.
(© 2014 American Neurological Association.)
Databáze: MEDLINE
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