Nine patients with KCNQ2-related neonatal seizures and functional studies of two missense variants

Abstract

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 in 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. We studied 104 patients with infantile-onset pharmacoresistant epilepsy who underwent exome or genome sequencing. Nine patients with neonatal-onset seizures from unrelated families were found to harbor pathogenic or likely pathogenic variants in the KCNQ2 gene. The p.(N258K) was recently reported, and p. (G279D) has never been previously reported. Functional effect of p.(N258K) and p.(G279D) has never been previously studied. 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 exerted dominant-negative effects in heterotetrameric with Kv7.3 channels. This study expands the mutational spectrum of KCNQ2- related epilepsy and their functional consequences provide insights into their pathomechanism.

Calcium‐sensing receptor regulates Kv7 channels via Gi/o protein signalling and modulates excitability of human induced pluripotent stem cell‐derived nociceptive‐like neurons

“…Based on the evidence that neuronal hyperexcitability is associated with dysfunctions of CaSR (Kapoor et al, 2008) and neuronal Kv7.2/7.3 channels (Chokvithaya et al, 2023;Schroeder et al, 1998), it is conceivable that a crosslink between CaSR and Kv7.2/7.3 channels exists and contributes to the regulation of neuronal excitability.…”

“…Based on the evidence that neuronal hyperexcitability is associated with dysfunctions of CaSR (Kapoor et al, 2008) and neuronal Kv7.2/7.3 channels (Chokvithaya et al, 2023; Schroeder et al, 1998), it is conceivable that a crosslink between CaSR and Kv7.2/7.3 channels exists and contributes to the regulation of neuronal excitability. This study aimed to establish the molecular pathway linking CaSR and Kv7.2/7.3 channels, and to explore the potential of calcilytics in suppressing neuronal hyperexcitability, using a human induced pluripotent stem cell (hiPSC)‐derived nociceptive‐like neuronal model.…”

Ca2+-sensing receptor regulates neuronal excitability via Kv7 channel and Gi/oprotein signalling

“…However, the well-established interplay between the CaSR and pro-inflammatory cytokines (Iamartino & Brandi, 2022) and the significance of the inflammatory process underlying many neuropathic pain conditions (Ellis & Bennett, 2013;Li et al, 2023) suggests the CaSR as a potential candidate for neuropathic pain therapy. Moreover, based on the evidence that neuronal hyperexcitability is associated with dysfunctions of the CaSR (Kapoor et al, 2008) and neuronal Kv7.2/7.3 channels (Chokvithaya et al, 2023;Maghera et al, 2020;Schroeder et al, 1998), it is conceivable that a crosslink between the CaSR and Kv7.2/7.3 channels may exist and contribute to the regulation of neuronal excitability. This study aimed to establish the molecular pathway linking the CaSR and Kv7.2/7.3 channels, and explore the potential of calcilytics in suppressing neuronal hyperexcitability using a human induced pluripotent stem cell (hiPSC)-derived nociceptive-like neuronal model.…”