Epilepsia. 2025 Apr 28. doi: 10.1111/epi.18427. Online ahead of print.
ABSTRACT
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.
PMID:40292751 | DOI:10.1111/epi.18427
