KCNA1

Molecular Characteristics

KCNA1 encodes the voltage-gated potassium channel subunit Kv1.1. Kv1.1 is a member of the voltage-gated, Shaker-related subfamily of potassium channels. These channels regulate neuron excitability by contributing to the resting membrane potential and allowing repolarization following an action potential. Kv channels are composed of four α subunits. Each subunit contains six transmembrane segments (S1–S6): the first four (S1–S4) comprise the voltage-sensor domain and S5, S6 and the S5–S6 linker form the pore region.

Most KCNA1 mutations are missense variants exerting a dominant negative effect which partially abolishes activity of the wild-type protein. No strong genotype-phenotype associations have been established in these disorders.

Epilepsy and seizure phenotypes appear to be restricted to mutations affecting the S1/S2 helices and pore domain of the Kv1.1 subunit, providing a possible explanation for epilepsy comorbidity in a subset of EA1 patients. Animal models demonstrate that genetic modifiers of KCNA1 mutations can also significantly impact disease manifestation and severity.