Mutations in KCNQ2 or KCNQ3 cause benign familial neonatal seizures (BFNS), a dominantly-inherited, highly penetrant early-onset epilepsy syndrome. BFNS causes frequent seizures during the neonatal period, but after seizures remit, affected individuals develop normally. However, compelling evidence now implicates a subset of KCNQ2 mutations in persistent and disabling CNS and neuromuscular diseases. KCNQ2 pedigrees exhibit painful myokymia (without seizures), myokymia after neonatal seizures, epilepsy after the neonatal period, and epilepsy with significant intellectual disability. Most importantly, a recent Euro-Australian collaborative study describes de novo KCNQ2 mutations in 10% of cases (8/80) of severe, sporadic, early- onset epileptic encephalopathy (EEE). As disclosed in this renewal application, our lab has ascertained 6 additional individuals from North America with EEE bearing novel KCNQ2 mutations. Although factors such as genetic background and epigenetics may influence these phenotypes, our analysis suggests mechanisms whereby the de novo KCNQ2 mutations in EEE patients may act as potent dominant-negatives, suppressing activity up to 94% (16-fold), whereas known BFNS mutations are known to generally reduce activity by 20-50% (2-fold or less). Here, we propose to define the developmental time course for the arrival of KCNQ2 and KCNQ3-containing channels at the axonal membrane of neurons in the hippocampal formation and the somatosensory and motor neocortex, assayed in normal rodents, KCNQ2 mutant mice, and human tissue. In parallel with anatomical study, we will also analyze the function of hippocampal and neocortical axonal KCNQ channels at the subcellular, cellular, and behavioral level through in vitro analysis, patch clamp recording, and transgenic animal models. Finally, we will analyze and compare the efficacy two KCNQ opener drugs which differ in potency, maximal efficacy and subunit specificity, to activate channels in vitro and terminate seizures in vivo.
Proteins called ion channels create the electrical signals in the brain that are the physical basis for activities such as thinking, sensation, and body movement. Ion channel variants can be responsible for several types of epilepsy which begin early after birth and are sometime followed by severe developmental delay. This study will analyze how variation in the ion channel called KCNQ2 cause such symptoms and test new strategies for treating and curing affected individuals, by using molecular biology, and studies of cells in culture and mice.
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