Key result
The KCNQ2 A265V variant caused reduced maximal current density, decreased voltage-dependence of activation, and a 50% current reduction during depolarizing pulses compared to wild-type channels.
Why the study?
De novo variants in KCNQ2 cause neonatal onset developmental and epileptic encephalopathy most often by loss-of-function in vitro effects, prompting investigation of a recurrent de novo KCNQ2 variant.
The study identifies current inactivation as a novel pathogenetic mechanism for KCNQ2-DEE caused by the recurrent A265V variant.
p.A265V alters Kv7.2 function in one DEE case; leaves open broader genotype-phenotype correlations and targeted therapies.
De novo variants in KCNQ2 cause neonatal onset developmental and epileptic encephalopathy (KCNQ2-DEE; Online Mendelian Inheritance in Man #613720), most often by loss-of-function in vitro effects. In this study, we describe a neonatal onset DEE proband carrying a recurrent de novo KCNQ2 variant (c.794C>T; p.A265V) affecting the pore domain of KCNQ2-encoded Kv7.2 subunits. Whole-cell patch-clamp measurement in a mammalian heterologous expression system revealed that, when compared to wild-type Kv7.2 channels, channels containing Kv7.2 A265V subunits displayed (1) reduced maximal current density; (2) decreased voltage-dependence of activation; and (3) an unusual inactivation process, with a 50% current reduction during 1-2-s depolarizing pulses at voltages > 0 mV. These effects were proportional to the number of mutant subunits incorporated in heteromeric channels, being overall less dramatic upon coexpression with Kv7.2 or Kv7.2 + Kv7.3 subunits. These results reveal current inactivation as a novel pathogenetic mechanism for KCNQ2-DEE caused by a recurrent variant affecting a critical pore residue, further highlighting the importance of in vitro functional assessment for a better understanding of disease molecular pathophysiology.
No takes yet. Share an insight, caveat, or question.
Gaspar et al. (2025) studied KCNQ2 developmental and epileptic encephalopathy (n=1). KCNQ2 variant (c.794C>T; p.A265V) vs. Wild-type Kv7.2 channels was evaluated on Potassium current characteristics (current density, voltage-dependence of activation, inactivation process). The KCNQ2 A265V variant caused reduced maximal current density, decreased voltage-dependence of activation, and a 50% current reduction during depolarizing pulses compared to wild-type channels.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: