KCNB1 encodes Kv2.1, a voltage-gated potassium channel that mediates delayed-rectifier potassium currents essential for action potential repolarization in neurons, pancreatic beta cells, and cardiovascular tissues 1. The channel functions as a homotetramer or heterotetrameric complex with other potassium channel subunits, displaying rapid activation and slow inactivation kinetics 23. Inactivation involves electromechanical coupling near the pore domain that repositions the internal S6 helices to close the channel 4. In neurons, KCNB1 regulates somatodendritic delayed-rectifier currents that suppress high-frequency firing and contribute to long-term potentiation in hippocampal CA3 neurons. In pancreatic beta cells, KCNB1 limits calcium influx and insulin secretion by modulating action potential properties 1. KCNB1 mutations cause developmental and epileptic encephalopathy (DEE), characterized by infantile-onset seizures, severe developmental delay, and intellectual disability 56. Most variants are de novo missense mutations affecting the voltage sensor or pore domain 67. Missense variants associate with more frequent and severe epilepsy compared to truncating variants 5. Seizure onset typically occurs before age two, with focal seizures predominating and approximately 76-81% of patients experiencing seizure clusters 75. While 57% achieve seizure control with antiepileptic drugs, long-term cognitive and behavioral outcomes remain poor 75. Additionally, KCNB1 oxidation is elevated in Alzheimer's disease brains and contributes to neurodegeneration 8.