KCNQ2 related-epilepsy: Report of nine cases and novel loss-of-function missense variants

Mutations in KCNQ2 encoding for voltage-gated K channel subunits underlying the neuronal M-current, have been associated with infantile-onset epileptic disorders. The clinical spectrum ranges from self-limited neonatal seizures to epileptic encephalopathy and delayed development. Mutations of KCNQ2 could be either gain- or loss-of-function which require different therapeutic approaches. To better understand genotype-phenotype correlation, more reports of patients and their mutations with elucidated molecular mechanism are needed. Here, we report nine unrelated patients with KCNQ2 -related epilepsy. Trio exome or genome sequencing successfully identified de novo heterozygous mutations in all patients. Two, p.N258K and p.G279D, had never been previously reported. The cellular localization study demonstrated that the surface membrane expression of Kv7.2 carrying either variant was decreased. Whole-cell patch-clamp analyses revealed that both variants significantly impaired Kv7.2 M-current amplitude and density, conductance depolarizing shift in voltage dependence of activation, membrane resistance, and membrane time constant (Tau), indicating a loss-of-function in both the homotetrameric and heterotetrameric with Kv7.3 channels. In addition, both variants also exerted dominant-negative effects in heterotetrameric with Kv7.3 channels. The two novel missense variants in KCNQ2 expand its mutational spectrum causing infantile-onset epileptic disorders and their functional consequences provide insights into their pathomechanism.