KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating

Abstract

Four KCND2 missense variants, identified in six unrelated individuals with early onset GDD, were functionally characterized. For this purpose, the respective Kv4.2 mutants with single amino acid substitutions, all at functionally relevant sites (E323K, P403A, V404L and V404M), were expressed in a heterologous system, and the currents were measured under two electrode voltage clamp. The mutant channels showed characteristic gating modifications both in the absence and presence of the auxiliary ß-subunits KChIP2 and DPP6, and auxiliary ß-subunit co-expression augmented the functional expression of both WT and mutant channels. In the heteromeric ternary configuration (co-expression of WT + mutant and simultaneous co-expression of both KChIP and DPP), which is referred to as the “native setting”, E323K displayed mild LOF, P403A and V404L a mixture of partial LOF and GOF features, and V404M only GOF features. The results of the present paper corroborate the functional importance of the S4-S5 linker and the distal S6 segment in Kv4.2 channel inactivation, they indicate a critical involvement of Kv4.2 channel dysfunction in the etiology of GDD, and they identify substitutions of V404 as likely determinants of epileptic seizure susceptibility. Thus, the present paper will support the development of early mechanism-based precision medicine to benefit young individuals and minimize developmental disturbances.