Multigenic, dominant-negative loss-of-function caused by an epilepsy-associated mutation in Kv1.2 (KCNA2)

Abstract

We have identified an epilepsy-associated mutation in KCNA2. This gene encodes the subunits of tetrameric voltage-gated potassium channel KV1.2, which controls neuronal excitability. Moreover, K+ conductance in the brain is diversified by the heteromerization of KV1.2 subunits with other members of the KV1 family. The mutation, F233S, is located at the well-conserved charge-transfer centre in helix S2. We previously reported that KV1.2(F233S) subunits have a severe trafficking deficiency. Here, we investigated how the mutation affects i) heteromeric KV1.2(WT/F233S)-channels, as in the heterozygous patient and ii) heteromers with known molecular associate KV1.4.