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

Gururaj, S; Palmer, EE; Sheehan, GD; Kandula, T; Macintosh, R; Ying, K; Morris, P; Tao, J; Dias, K-R; Zhu, Y; Dinger, ME; Cowley, MJ; Kirk, EP; Roscioli, T; Sachdev, R; Duffey, ME; Bye, A; Bhattacharjee, A

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

Gururaj, S Palmer, EE Sheehan, GD Kandula, T Macintosh, R Ying, K

Morris, P Tao, J Dias, K-R Zhu, Y Dinger, ME Cowley, MJ Kirk, EP Roscioli, T Sachdev, R Duffey, ME Bye, A Bhattacharjee, A

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: Cell Reports, 2017, 21, (4), pp. 926-933
Issue Date:: 2017-10-24

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Field	Value	Language
dc.contributor.author	Gururaj, S
dc.contributor.author	Palmer, EE
dc.contributor.author	Sheehan, GD
dc.contributor.author	Kandula, T
dc.contributor.author	Macintosh, R
dc.contributor.author	Ying, K https://orcid.org/0000-0001-6041-8773
dc.contributor.author	Morris, P
dc.contributor.author	Tao, J
dc.contributor.author	Dias, K-R
dc.contributor.author	Zhu, Y
dc.contributor.author	Dinger, ME
dc.contributor.author	Cowley, MJ
dc.contributor.author	Kirk, EP
dc.contributor.author	Roscioli, T
dc.contributor.author	Sachdev, R
dc.contributor.author	Duffey, ME
dc.contributor.author	Bye, A
dc.contributor.author	Bhattacharjee, A
dc.date.accessioned	2022-09-13T01:47:24Z
dc.date.available	2017-09-26
dc.date.available	2022-09-13T01:47:24Z
dc.date.issued	2017-10-24
dc.identifier.citation	Cell Reports, 2017, 21, (4), pp. 926-933
dc.identifier.issn	2211-1247
dc.identifier.issn	2211-1247
dc.identifier.uri	http://hdl.handle.net/10453/161773
dc.description.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 KNa channels. These findings establish pathogenicity of the Phe240Leu KCNT2 mutation in the reported EOEE patient.
dc.format	Print
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	Cell Reports
dc.relation.isbasedon	10.1016/j.celrep.2017.09.088
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 1116 Medical Physiology
dc.subject.mesh	Action Potentials
dc.subject.mesh	Animals
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Child, Preschool
dc.subject.mesh	CHO Cells
dc.subject.mesh	Cricetinae
dc.subject.mesh	Cricetulus
dc.subject.mesh	Epilepsy
dc.subject.mesh	Female
dc.subject.mesh	Heterozygote
dc.subject.mesh	Humans
dc.subject.mesh	Male
dc.subject.mesh	Mutation, Missense
dc.subject.mesh	Phenotype
dc.subject.mesh	Potassium
dc.subject.mesh	Potassium Channels
dc.subject.mesh	Potassium Channels, Sodium-Activated
dc.subject.mesh	Rats
dc.subject.mesh	Rats, Sprague-Dawley
dc.subject.mesh	Sodium
dc.subject.mesh	Xenopus
dc.subject.mesh	Action Potentials
dc.subject.mesh	Animals
dc.subject.mesh	CHO Cells
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Cricetinae
dc.subject.mesh	Cricetulus
dc.subject.mesh	Epilepsy
dc.subject.mesh	Female
dc.subject.mesh	Heterozygote
dc.subject.mesh	Humans
dc.subject.mesh	Male
dc.subject.mesh	Mutation, Missense
dc.subject.mesh	Phenotype
dc.subject.mesh	Potassium
dc.subject.mesh	Potassium Channels
dc.subject.mesh	Potassium Channels, Sodium-Activated
dc.subject.mesh	Rats
dc.subject.mesh	Rats, Sprague-Dawley
dc.subject.mesh	Sodium
dc.subject.mesh	Xenopus
dc.subject.mesh	Cells, Cultured
dc.subject.mesh	CHO Cells
dc.subject.mesh	Animals
dc.subject.mesh	Xenopus
dc.subject.mesh	Humans
dc.subject.mesh	Cricetulus
dc.subject.mesh	Rats
dc.subject.mesh	Rats, Sprague-Dawley
dc.subject.mesh	Epilepsy
dc.subject.mesh	Potassium
dc.subject.mesh	Sodium
dc.subject.mesh	Potassium Channels
dc.subject.mesh	Action Potentials
dc.subject.mesh	Heterozygote
dc.subject.mesh	Phenotype
dc.subject.mesh	Mutation, Missense
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Female
dc.subject.mesh	Cricetinae
dc.subject.mesh	Male
dc.subject.mesh	Potassium Channels, Sodium-Activated
dc.title	A De Novo Mutation in the Sodium-Activated Potassium Channel KCNT2 Alters Ion Selectivity and Causes Epileptic Encephalopathy.
dc.type	Journal Article
utslib.citation.volume	21
utslib.location.activity	United States
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1116 Medical Physiology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - AIMI - Australian Institute for Microbiology & Infection
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2022-09-13T01:47:20Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	21
utslib.citation.issue	4

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

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http://hdl.handle.net/10453/161773