GABAA Receptor Subunit Mutations and Genetic Epilepsies

Excerpt

Mutations in inhibitory GABA_A receptor subunit genes (GABRA1, GABRB3, GABRG2 and GABRD) have been associated with idiopathic epilepsy syndromes (IES) including childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), pure febrile seizures (FS), generalized epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS) (also known as severe myoclonic epilepsy in infancy, SMEI). These mutations are found in both translated and untranslated gene regions and have been shown to affect the GABA_A receptors by altering receptor function and/or by impairing receptor biogenesis by multiple mechanisms including reducing subunit mRNA transcription or stability, impairing subunit folding, stability, or oligomerization or by inhibiting receptor trafficking. While a clear genotype/phenotype correlation has not been established, mutations of GABRB3 and GABRA1 are associated with CAE or JME while mutations and variants of GABRG2 and GABRD are associated with FS, FS with CAE, GEFS+, and DS.