Point mutations in the voltage-gated potassium channel Kv7.2/7.3, and their possible involvement in epilepsy and channel gating

Benign familial neonatal epilepsy (BFNE) is a genetic disorder that causes seizures, starting during the 3rd - 7th day after birth. Most of the causes of this condition are associated with a malfunction of the M-channel, a heteromeric potassium channel consisting of Kv7.2 and Kv7.3 subunits. The demand for better antiepileptic drugs has made this channel an important target to be explored, equally to treat BFNE as well as some other forms of epilepsy. Understanding in detail the function of this channel in health and disease is fundamental to develop new and more effective drug treatments. Using a combination of mutagenesis, concatemers, molecular modeling, and two-electrode voltage clamp electrophysiology we have characterized some functional aspects of mutations, identified on the ClinVar database as pathogenic or likely pathogenic. The identity and location of these mutations, and how they affect channel function, may guide us to a deeper understanding of the severity of this disease. These mutations also suggest which biophysical properties are important for normal gating and stability in the membrane. Here we describe a significant reduction in the magnitude of the current as a direct consequence of the mutations and discuss some of the possible mechanistic reasons for this reduction.