Pharmacology and Toxicology, University at Buffalo - The State University of New York, Buffalo, NY 14214, USA.
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.
Cell Rep. 2017 Oct 24;21(4):926-933. 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] 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 channels. These findings establish pathogenicity of the Phe240Leu KCNT2 mutation in the reported EOEE patient.
早期婴儿癫痫性脑病 (EOEE) 是一种与认知障碍相关的致残性疾病谱。我们报告了一名 EOEE 患者中 KCNT2 突变的临床病例。通过外显子组测序鉴定到新生杂合突变 Phe240Leu SLICK，并通过 Sanger 测序进行了确认。对 Phe240Leu rSlick 和 hSLICK 通道进行了电生理异源表达，揭示了三个对通道功能有显著影响的改变。首先，Phe240Leu 通道的[Cl]敏感性发生了反转。其次，Phe240Leu 使 WT 通道主要具有 K 选择性，转而有利于 Na 而不是 K。第三，由于离子选择性的改变，Phe240Leu 通道的内向电导增大。此外，rSlick 通道在原代神经元中表达时会引起膜过度兴奋，类似于细胞癫痫表型。总之，我们的结果证实 Phe240Leu 是一种“功能改变”的 KCNT2 突变，表明 K 通道的选择性发生了异常改变。这些发现确立了 Phe240Leu KCNT2 突变在报告的 EOEE 患者中的致病性。
