A reduced K+ current due to a novel mutation in KCNQ2 causes neonatal convulsions

Benign familial neonatal convulsions (BFNC) is a rare dominantly inherited epileptic syndrome characterized by frequent brief seizures within the firs t days of life. The disease is caused by mutations in one of two recently i dentified voltage-gated potassium channel genes, KCNQ2 or KCNQ3. Here, we d escribe a four-generation BFNC family carrying a novel mutation within the distal, unconserved C-terminal domain of KCNQ2, a 1-bp deletion, 2513delG, in codon 838 predicting substitution of the last seven and extension by ano ther 56 amino acids. Three family members suffering from febrile but not fr om neonatal convulsions do not carry the mutation, confirming that febrile convulsions and BFNC are of different parhogenesis. Functional expression o f the mutant channel in Xenopus oocytes revealed a reduction of the potassi um current to 5% of the wild-type current, but the voltage sensitivity and kinetics were not significantly changed. To find out whether the loss of th e last seven amino acids or the C-terminal extension because of 2513delG ca uses the phenotype, a second, artificial mutation was constructed yielding a stop codon at position 838. This truncation increased the potassium curre nt by twofold compared with the wild type, indicating that the pathological extension produces the phenotype, and suggesting an important role of the distal, unconserved C-terminal domain of this channel. Our results indicate that BFNC is caused by a decreased potassium current impairing repolarizat ion of the neuronal cell membrane, which results in hyperexcitability of th e central nervous system.