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

Cell Rep. 2017 Oct 24;21(4):926-933. doi: 10.1016/j.celrep.2017.09.088.

Sushmitha Gururaj ¹, Elizabeth Emma Palmer ², Garrett D Sheehan ¹, Tejaswi Kandula ³, Rebecca Macintosh ⁴, Kevin Ying ⁵, Paula Morris ⁵, Jiang Tao ⁵, Kerith-Rae Dias ⁵, Ying Zhu ⁶, Marcel E Dinger ⁷, Mark J Cowley ⁷, Edwin P Kirk ⁸, Tony Roscioli ⁸, Rani Sachdev ³, Michael E Duffey ⁹, Ann Bye ³, Arin Bhattacharjee ¹⁰

Affiliations

1 Pharmacology and Toxicology, University at Buffalo - The State University of New York, Buffalo, NY 14214, USA.
2 Sydney Children's Hospital, Randwick, NSW 2031, Australia; University of New South Wales, Sydney, NSW 2031, Australia; Genetics of Learning Disability Service, Waratah, NSW 2298, Australia.
3 Sydney Children's Hospital, Randwick, NSW 2031, Australia; University of New South Wales, Sydney, NSW 2031, Australia.
4 Sydney Children's Hospital, Randwick, NSW 2031, Australia.
5 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2298, Australia.
6 Genetics of Learning Disability Service, Waratah, NSW 2298, Australia; SEALS Pathology, Randwick, NSW 2031, Australia.
7 University of New South Wales, Sydney, NSW 2031, Australia; Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW 2298, Australia.
8 Sydney Children's Hospital, Randwick, NSW 2031, Australia; University of New South Wales, Sydney, NSW 2031, Australia; SEALS Pathology, Randwick, NSW 2031, Australia.
9 Physiology and Biophysics, University at Buffalo - The State University of New York, Buffalo, NY 14214, USA.
10 Pharmacology and Toxicology, University at Buffalo - The State University of New York, Buffalo, NY 14214, USA; Program for Neuroscience, University at Buffalo - The State University of New York, Buffalo, NY 14214, USA. Electronic address: ab68@buffalo.edu.

PMID: 29069600 DOI: 10.1016/j.celrep.2017.09.088

Abstract

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 K_Na channels. These findings establish pathogenicity of the Phe240Leu KCNT2 mutation in the reported EOEE patient.

Keywords

KCNT1; KCNT2; Slack; Slick; Xenopus oocytes; epileptic encephalopathy; ion channels; potassium channels; seizures; selectivity.

Name
Email *

	Sorry, but the email address you supplied was invalid.