| dc.description.abstract | Epilepsy is a neurological disorder affecting almost one percent of the population, and genetic epilepsy are those caused by a presumed or unknown genetic factor(s). Mutations in GABAA receptors, pentameric chloride ion channels mediating fast inhibitory neurotransmission, have been identified in patients and families with epilepsy and found to cause epilepsy in animal models. The majority of synaptic GABAARs are αβγ type receptors composed of two α, two β and one γ2 subunits, and half of these epilepsy-associated GABAAR mutations are located in γ2 subunits encoded by the GABRG2 gene. A better understanding of how different types of epilepsy-associated GABRG2 mutations affect receptor trafficking and channel function, and how these mutations cause epilepsy in mouse models, will facilitate future epilepsy diagnosis as well as treatments. Here we have studied three different types of mutations represented by GABRG2(N79S, R82Q, and P83S), GABRG2(Q40X), and GABRG2(Q390X), in cultured HEK cells or animal models. We found that missense mutations located in receptor interface will disrupt receptor assembly and trafficking, which may be improved by slowing receptor biogenesis. We found that nonsense mutations showing loss of function could be partially rescued using gentamicin-induced stop codon read-through. Finally we showed that gene-target therapy could reverse the seizure phenotype in a mouse model carrying a detrimental mutation with dominant negative effects. To conclude, we have shown different molecular mechanisms are associated with these mutations, and distinct mutation-specific therapy may be potentially developed for future treatments. | |
