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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Gururaj S,Palmer EE,Sheehan GD,Kandula T,Macintosh R,Ying K,Morris P,Tao J,Dias KR,Zhu Y,Dinger ME,Cowley MJ,Kirk EP,Roscioli T,Sachdev R,Duffey ME,Bye A,Bhattacharjee Adoi
10.1016/j.celrep.2017.09.088subject
Has Abstractpub_date
2017-10-24 00:00:00pages
926-933issue
4issn
2211-1247pii
S2211-1247(17)31408-0journal_volume
21pub_type
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