Idiopathic absence epilepsies (IAE), that have high prevalence particularly among children and adolescents, are complex disorders mainly caused by genetic factors. Childhood absence epilepsy and juvenile absence epilepsy are among the most common subtypes of IAEs. While the role of ion channels has been the primary focus of epilepsy research, the analysis of mutation and association in both patients with absence epilepsies and animal models revealed the involvement of GABA receptors and calcium channels, but also of novel non-ion channel proteins in inducing spike wave discharges (SWD). Functional studies on a mutated variant of these proteins also support their role in the epileptogenesis of absence seizures. Studies in animal models point to both the thalamus and cortex as the origin of SWDs: the abnormalities in the components of these circuits leading to seizure activity. This review examines the current research on mutations and susceptibility alleles determined in the genes that code for the subunits of GABA receptors (GABRG2, GABRA1, GABRB3, GABRA5, GABA(B1) and GABA(B2)), calcium channels (CACNA1A, CACNA1G, CACNA1H, CACNA1I, CACNAB4, CACNAG2 and CACNG3), and novel non-ion channel proteins, taking into account the results of functional studies on these variants.

Benign familial neonatal seizures (BFNS) is a dominant epilepsy syndrome caused by mutations in the voltage-gated potassium channels K V 7.2 and K V 7.3. We examined the molecular pathomechanism of a BFNS-causing mutation (p.N258S) in the extracellular S5-H5 loop of K V 7.2. Wild type (WT) and mutant channels, expressed in both Xenopus laevis oocytes and CHO cells, were studied using electrophysiological techniques. The results revealed a pronounced loss-offunction with a dominant-negative effect of the mutant on WT K V 7.2 and K V 7.3 channels. Since single channel recordings of K V 7.3-K V 7.2 and K V 7.3-N285S concatemers showed similar properties for both constructs, we hypothesized that the observed reduction in current amplitude was due to a folding and trafficking defect, which was confirmed by biochemical and immunocytochemical experiments revealing a reduced number of mutant channels in the surface membrane. Furthermore, rescuing experiments revealed that upon specific incubation of transfected CHO cells -either at lower temperatures of <30 o C or in presence of the agonist retigabine -the N258S-derived currents increased 5-fold in contrast to the WT. The obtained results represent a first example of temperature and pharmacological rescue of a K V 7 mutation and suggest a folding and trafficking deficiency as the cause of reduced current amplitudes with a dominant-negative effect of N258S mutant proteins.

Summary Purpose:  To further evaluate the previously shown linkage of absence epilepsy (AE) to 2q36, both in human and WAG/Rij absence rat models, a 160‐kb region at 2q36 containing eight genes with expressions in the brain was targeted in a case–control association study involving 205 Turkish patients with AE and 219 controls. Methods:  Haplotype block and case–control association analysis was carried out using HAPLOVIEW 4.0 and inhibin alpha subunit (INHA) gene analysis by DNA sequencing. Key Findings:  An association was found between the G allele of rs7588807 located in the INHA gene and juvenile absence epilepsy (JAE) syndrome and patients having generalized tonic–clonic seizures (GTCS) with p‐values of 0.003 and 0.0002, respectively (uncorrected for multiple comparisons). DNA sequence analysis of the INHA gene in 110 JAE/GTCS patients revealed three point mutations with possible damaging effects on inhibin function in three patients and the presence of a common ACTC haplotype (H1) with a possible dominant protective role conferred by the T allele of rs7588807 with respective p‐values of 0.0005 and 0.0014. Significance:  The preceding findings suggest that INHA could be a novel candidate susceptibility gene involved in the pathogenesis of JAE or AE associated with GTCS.

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