GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies

Dibbens, Leanne M.; Feng, Huajun; Richards, Michaella C.; Harkin, Louise A.; Hodgson, Bree; Scott, Darren; Jenkins, Misty R.; Petrou, Steven; Sutherland, Grant R.; Scheffer, Ingrid E.; Berkovic, Samuel F.; Macdonald, Robert L.; Mulley, John C.

doi:10.1093/hmg/ddh146

Cited by 314 publications

(214 citation statements)

References 25 publications

Supporting

Mentioning

206

Contrasting

Unclassified

Order By: Relevance

“…183 Mutations involving the ␥2 subunit in two cases associated with GEFSϩ and in two cases associated with childhood absence epilepsy with febrile convulsions have been found to alter the kinetic properties of the receptor and also their surface expression. 183 Three mutations in families with GEFSϩ involving the ␦ subunit 185 are associated with reduced current, suggesting that impairment of tonic inhibition by extrasynaptic GABA receptors can also produce epilepsy. Studies in genetically modified mice have revealed spontaneous seizures in ␤3 knockout mice, 186 supporting the interpretation that the seizures that are a prominent feature of the Angelman syndrome (which, in addition to other genetic abnormalities, lacks the ␤3 gene) are due specifically to defects in GABA A receptors.…”

Section: Cys-loop Ligand-gated Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

View full text Add to dashboard Cite

Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

show abstract

Section: Cys-loop Ligand-gated Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

View full text Add to dashboard Cite

show abstract

“…Recent studies have demonstrated that defects in receptor function or tonic inhibition resulted in neurological disorders such as epilepsy [349,350]. Studies regarding the genetics of human epilepsy demonstrated that various heritable mutations in GABA A receptor subunits are associated with epilepsy [351].…”

Section: Gaba Receptorsmentioning

confidence: 99%

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

View full text Add to dashboard Cite

Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

show abstract

“…Listing only those involving the Na V family and associated subunits; GEFS + Type 1 is associated with mutations to SCN1B encoding the β 1 subunit of Na V ; GEFS + Type 2 with SCN1A encoding Na V 1.1; and GEFS + Type 7 with SCN9A encoding Na V 1.7. [68][69][70] The phenotypes associated with the various GEFS + mutations vary between affected individuals, but the most common symptoms are febrile seizures (FS). As mentioned previously, FS are quite common in young children and have an age dependent decrease in prevalence.…”

Section: Gefs +mentioning

confidence: 99%