Mutations in KCNB1, encoding the brain potassium channel KV2.1, have recently been discovered as the cause of epileptic encephalopathy type 26 (EIEE26). Six mutations, including S347R, have been reported so far and at least 7 additional novel variants have been identified. Electrophysiological studies in heterologous cell systems have demonstrated a prominent loss-of-function for most of the mutations and variants, with evidence of dominant-negative effects on the wild-type allele. Further, those mutations affecting the pore domain of the channel exhibit additional functional features including loss of ion selectivity. These findings support the hypothesis that epileptic encephalopathy associated with KCNB1 mutations arises because of loss-of-function and suggest that Kv2.1 channel activators may have therapeutic value in subjects with these mutations. A systematic screen of existing approved drugs and other known potassium channel modulators could reveal near and long term opportunities for therapeutic intervention.
|Effective start/end date||12/11/15 → 12/11/16|
- Pairnomix, LLC (Agmt 12/11/15)
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