GABAA receptor mutations in epilepsy (Commentary on Lachance‐Touchette et al.)

Abstract

Although idiopathic epilepsy has long been known to have high heritability, the first gene was not identified until 1995 (Steinlein et al., 1995), a breakthrough that started to unravel the genetic architecture of this disease. Whereas some evidence exists for a genetic component of the focal epilepsies, a more complete understanding is emerging for generalized syndromes. Indeed, a re-classification of idiopathic generalized epilepsy (IGE) to genetic generalized epilepsy has been recently proposed, highlighting the importance of genetic mechanisms in this disease (Berg et al., 2010). Strikingly, the overwhelming majority of genes identified have encoded ion channels, both voltage-gated and ligand-gated. In this issue of the European Journal of Neuroscience, Lachance-Touchette et al. (2011) add to our understanding of the role of genetic variability of GABAA receptors in IGE by describing three novel mutations. Although many puzzles remain, these ‘epileptic channelopathies’ provide the most compelling insights into the causation of a serious neurological disorder. Lachance-Touchette et al. (2011) screened three French Canadian families with IGE for mutations in GABRA1 and GABRG2, which encode the a1 and c2 subunits of the GABAA receptor, respectively. These subunits co-assemble together with b subunits to make up an abundant receptor subtype expressed in the forebrain. The authors report two previously unreported mutations in GABRA1, and the results of functional analysis are consistent with a reduction in cell surface expression of the mature protein in both cases. Only two previous GABRA1 mutations have been reported, one a familial mutation associated with juvenile myoclonic epilepsy (Cossette et al., 2002), and another in a sporadic case of childhood absence seizures (Maljevic et al., 2006). Interestingly, the seizure phenotypes of the families harbouring the newly reported mutations are different, and include febrile seizures, generalized tonic–clonic seizures and photosensitive seizures. This broad seizure spectrum occurs despite a common mutation-mediated loss of protein function. Clinical heterogeneity is a common feature of the ‘monogenic’ causes of epilepsy, and strongly suggests that other genetic factors are critical in defining seizure outcome (Reid et al., 2009). Lachance-Touchette et al. (2011) also describe a novel GABRG2 mutation in a large family with febrile seizures and IGE. The mutation is found in all nine affected individuals, so it comes as some surprise that they are unable to identify a functional deficit. This is particularly true given the proximity of the mutation to a well-validated GABRG2 variant in a family with a similar spectrum of seizures (Wallace et al., 2001). LachanceTouchette et al. (2011) confirm that the receptors are insensitive to Zn and are potentiated by diazepam, important controls to show that the c2 subunit is incorporated into GABAA receptors at the cell surface. The mutation is highly unlikely to be a rare polymorphism, because it affects a conserved residue and co-segregates with the phenotype. So how can the lack of functional effect be reconciled with a causative role in epilepsy? A possible explanation is that the experiments were performed at room temperature. Indeed, there is a precedent for a febrile seizure-associated GABRG2 mutation only altering trafficking at higher temperatures (Kang et al., 2006). Another subtlety of GABRG2 mutations is that their functional consequences can differ with the identity of the co-expressed GABAA receptor a subunits. For example, the GABAAc2 (R43Q) mutation has no impact on a1 expression (Tan et al., 2007), whereas the same mutated protein reduces a5 surface expression (Eugene et al., 2007), and may also alter the stoichiometry of GABAA receptors containing the a3 subunit (Frugier et al., 2007). Because Lachance-Touchette et al. (2011) only examined a1 subunit-containing GABAA receptors, this leaves open the possibility that altered channel expression or function could be revealed by other combinations of subunits. Despite the fact that ‘monogenic’ causes of epilepsy in large families are rare, the epilepsy syndromes that they exhibit are common. This has provided a ‘fast-track’ to begin our understanding of the genetic architecture of epilepsy. The work of Lachance-Touchette et al. (2011) substantially expands our understanding of the causation of IGE, and will help in our quest to unravel the cellular and circuit mechanisms underlying this common disease.