title: Mutations affecting GABAergic signaling in seizures and epilepsy.
abstract: The causes of epilepsies and epileptic seizures are multifactorial. Genetic predisposition may contribute in certain types of epilepsies and seizures, whether idiopathic or symptomatic of genetic origin. Although these are not very common, they have offered a unique opportunity to investigate the molecular mechanisms underlying epileptogenesis and ictogenesis. Among the implicated gene mutations, a number of GABAA receptor subunit mutations have been recently identified that contribute to several idiopathic epilepsies, febrile seizures, and rarely to certain types of symptomatic epilepsies, like the severe myoclonic epilepsy of infancy. Deletion of GABAA receptor genes has also been linked to Angelman syndrome. Furthermore, mutations of proteins controlling chloride homeostasis, which indirectly defines the functional consequences of GABAA signaling, have been identified. These include the chloride channel 2 (CLCN2) and the potassium chloride cotransporter KCC3. The pathogenic role of CLCN2 mutations has not been clearly demonstrated and may represent either susceptibility genes or, in certain cases, innocuous polymorphisms. KCC3 mutations have been associated with hereditary motor and sensory polyneuropathy with corpus callosum agenesis (Andermann syndrome) that often manifests with epileptic seizures. This review summarizes the recent progress in the genetic linkages of epilepsies and seizures to the above genes and discusses potential pathogenic mechanisms that contribute to the age, sex, and conditional expression of these seizures in carriers of these mutations.
authors.affiliation: Saul R. Korey Department of Neurology and Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Kennedy Center Room 306, Bronx, NY 10461, USA. aristea.galanopoulou@einstein.yu.edu
authors.forename: Aristea S
authors.initials: AS
authors.lastname: Galanopoulou
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D000090007:CLC-2 Chloride Channels; D053447:Channelopathies / Q000235:genetics / Q000503:physiopathology; D018118:Chloride Channels / Q000235:genetics / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D004831:Epilepsies, Myoclonic / Q000235:genetics / Q000503:physiopathology; D004827:Epilepsy / Q000235:genetics*; D006801:Humans; D009154:Mutation; D011963:Receptors, GABA-A / Q000235:genetics* / Q000502:physiology*; D018080:Receptors, GABA-B / Q000235:genetics* / Q000502:physiology*; D012640:Seizures / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D027981:Symporters / Q000235:genetics / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology; D000096922:K Cl- Cotransporters
chemical_list: D000090007:CLC-2 Chloride Channels; D018118:Chloride Channels; D002712:Chlorides; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D027981:Symporters; D005680:gamma-Aminobutyric Acid; C119650:SLC12A6 protein, human; D000096922:K Cl- Cotransporters