Özet:
Idiopathic absence epilepsies (IAE) are complex disorders mainly caused by genetic factors. Two major whole-genome linkage studies performed on many IAE samples pointed to chromosome 2q36 as a susceptibility locus for absence epilepsies. Whole genome linkage study on absence epilepsy model Wag/Rij rats, also showed the syntenic 2q33-37 region to be linked to the quantative trait of absence seizures. Candidate ion channel genes at 2q36 were screened but causative mutation could not be identified. On the other hand, mutations have been found in the subunits of GABA receptors and Ca channels in a few patients. At present, therefore, the complete picture of pathogenesis of the absence seizures is not known. In this study, to assess the possible role of 2q36 region in absence epilepsy, 205 Turkish absence patients and 219 healthy controls were used in an association analysis. Based on the haplotype block structure of the Turkish population in this region 10 tagSNPs were selected to cover the 160kb region at 2q36. The patients were subgrouped according to the syndrome and seizure types. The results revealed a significant association of two neighboring SNPs (rs7588807 and rs2840128) with JAE syndrome and even higher significant association with GTCS with the same SNP, rs7588807 that resided in the INHA gene. The point mutation and qPCR analysis of the INHA gene revealed mutations/variations in several patients and a large deletion that covered 30-50 kb in at least seven JAE patients supporting the association of INHA with the epilepsy phenotype and its establishment as a novel gene involved in the pathogenesis of JAE. The presence of other candidate genes in the deleted region paves the way for further molecular genetic analysis to reveal the role of each candidate gene in the pathogenesis of epilepsies, if any. The study further supports the role of GABRG2 in the pathogenesis of absence seizures by the identification of novel variations/mutations especially affecting the splice sites in CAE patients.
