Generalized epilepsy with febrile seizures plus-associated sodium channel β1 subunit mutations severely reduce beta subunit-mediated modulation of sodium channel function

Abstract

Two novel mutations (R85C and R85H) on the extracellular immunoglobulin-like domain of the sodium channel β1 subunit have been identified in individuals from two families with generalized epilepsy with febrile seizures plus (GEFS+). The functional consequences of these two mutations were determined by co-expression of the human brain NaV1.2 α subunit with wild type or mutant β1 subunits in human embryonic kidney (HEK)-293T cells. Patch clamp studies confirmed the regulatory role of β1 in that relative to NaV1.2 alone the NaV1.2+β1 currents had right-shifted voltage dependence of activation, fast and slow inactivation and reduced use dependence. In addition, the NaV1.2+β1 current entered fast..