Ion Channel Genes and Epilepsy: Functional Alteration, Pathogenic Potential, and Mechanism of Epilepsy

Abstract

Ion channels are crucial in the generation and modulation of excitability in the nervous system and have been implicated in human epilepsy. Forty-one epilepsy-associated ion channel genes and their mutations are systematically reviewed. In this paper, we analyzed the genotypes, functional alterations (funotypes), and phenotypes of these mutations. Eleven genes featured loss-of-function mutations and six had gain-of-function mutations. Nine genes displayed diversified funotypes, among which a distinct funotype-phenotype correlation was found in SCN1A. These data suggest that the funotype is an essential consideration in evaluating the pathogenicity of mutations and a distinct funotype or funotype-phenotype correlation helps to define the pathogenic potential of a gene.

Novel mutations and phenotypes of epilepsy‐associated genes in epileptic encephalopathies

“…Functional studies have showed that all KCNT1 mutations led to gain of function, except one that caused loss of function and was identified in a case of severe early infantile epileptic encephalopathy and leukoencephalopathy . Currently, the function alteration of SCN2A mutations identified in epileptic encephalopathies is uncertain . In this study, 4 genes including KCNT1 , SCN2A , KCNQ2 and CLCN4 were identified as putatively causative genes.…”

“…35 Currently, the function alteration of SCN2A mutations identified in epileptic encephalopathies is uncertain. 34 In this study, 4 genes including KCNT1, SCN2A, KCNQ2 and CLCN4 were identified as putatively causative genes. Mutations of KCNQ2 and CLCN4 were not heretofore reported in patients with EIMFS.…”

“… KCNT1 and SCN2A mutations are the most frequent causes of EIMFS, explaining about 50% and 25% of cases, respectively . Functional studies have showed that all KCNT1 mutations led to gain of function, except one that caused loss of function and was identified in a case of severe early infantile epileptic encephalopathy and leukoencephalopathy . Currently, the function alteration of SCN2A mutations identified in epileptic encephalopathies is uncertain .…”

Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature

“…Recent advances in DNA‐sequencing methods have highlighted the important role of gene‐encoding ion channels in the pathogenesis of DEEs (Wang et al, ). Ion channels are crucial in the generation and modulation of excitability in the nervous system (Wei et al, ). “Channelopathies” are associated with a wide phenotypic and genotypic spectrum as one gene is often associated with different phenotypes and variants in several genes might result in the same epilepsy phenotype (McTague, Howell, Cross, Kurian, & Scheffer, ; Wei et al, ).…”

Progressive myoclonus epilepsy caused by a gain-of-function KCNA2 mutation

“…The potassium channel dysfunctions involved in the other PME phenotypes have been demonstrated by studies aimed at characterising mutated KCNC1 and KTCD7. 4 It can be assumed that the c.890 G > A mutation in the KCNA2 channel (a member of the delayed rectifier class of potassium channels) leads to a gain of function by greatly increasing the potassium current and shifting its activation to more hyperpolarised potentials. The effect of the increased neuronal excitability is currently unclear, [4] but it may involve complex local mechanisms or circuitry rearrangements such as those leading to changes in channel inactivation at nearly resting potentials in excitatory neurons or a decrease in the excitability of inhibitory neurons.…”