RGD Reference Report - A De Novo Mutation in the Sodium-Activated Potassium Channel KCNT2 Alters Ion Selectivity and Causes Epileptic Encephalopathy. - Rat Genome Database

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A De Novo Mutation in the Sodium-Activated Potassium Channel KCNT2 Alters Ion Selectivity and Causes Epileptic Encephalopathy.

Authors: Gururaj, Sushmitha  Palmer, Elizabeth Emma  Sheehan, Garrett D  Kandula, Tejaswi  Macintosh, Rebecca  Ying, Kevin  Morris, Paula  Tao, Jiang  Dias, Kerith-Rae  Zhu, Ying  Dinger, Marcel E  Cowley, Mark J  Kirk, Edwin P  Roscioli, Tony  Sachdev, Rani  Duffey, Michael E  Bye, Ann  Bhattacharjee, Arin 
Citation: Gururaj S, etal., Cell Rep. 2017 Oct 24;21(4):926-933. doi: 10.1016/j.celrep.2017.09.088.
RGD ID: 13792534
Pubmed: (View Article at PubMed) PMID:29069600
DOI: Full-text: DOI:10.1016/j.celrep.2017.09.088

Early infantile epileptic encephalopathies (EOEE) are a debilitating spectrum of disorders associated with cognitive impairments. We present a clinical report of a KCNT2 mutation in an EOEE patient. The de novo heterozygous variant Phe240Leu SLICK was identified by exome sequencing and confirmed by Sanger sequencing. Phe240Leu rSlick and hSLICK channels were electrophysiologically, heterologously characterized to reveal three significant alterations to channel function. First, [Cl-]i sensitivity was reversed in Phe240Leu channels. Second, predominantly K+-selective WT channels were made to favor Na+ over K+ by Phe240Leu. Third, and consequent to altered ion selectivity, Phe240Leu channels had larger inward conductance. Further, rSlick channels induced membrane hyperexcitability when expressed in primary neurons, resembling the cellular seizure phenotype. Taken together, our results confirm that Phe240Leu is a "change-of-function" KCNT2 mutation, demonstrating unusual altered selectivity in KNa channels. These findings establish pathogenicity of the Phe240Leu KCNT2 mutation in the reported EOEE patient.

Annotation

Gene Ontology Annotations    

Biological Process

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Kcnt2  (potassium sodium-activated channel subfamily T member 2)


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