Association of the 867Asp variant of the human anion exchanger 3 gene with common subtypes of idiopathic generalized epilepsy.

Genetic factors play a major role in the etiology of idiopathic generalized epilepsies (IGE). Our recent genome-wide search revealed suggestive evidence for a susceptibility locus for common IGE syndromes in the chromosomal region 2q36. The gene encoding the anion exchanger isoform 3 (AE3; gene symbol: SLC4A3) has been mapped to this candidate region. AE3 is prominently expressed in the brain and performs an electroneutral exchange of chloride and bicarbonate. To study the potential role of AE3 in the epileptogenesis of IGE, we performed a mutation analysis of the AE3 coding region, including the adjacent exon/intron boundaries, and the 5'-untranslated region in 16 IGE probands of families linked to chromosome 2q36 (cumulative two-point lod score: Z=5.32 at D2S371). Three exonic sequence variants were found: exon 17: 2600C/A, Ala867Asp; exon 21: 3391C/T, Leu1131Leu; exon 23: 3771G/A, 3'-UTR. Our subsequent population-based association study of the Ala867Asp substitution polymorphism revealed a significant increase of the 867Asp variant in 366 unrelated German IGE patients compared with 183 German control subjects (chi(2)=5.37, df=1, P=0.021). Consistently, the transmission disequilibrium test (TDT) of 121 parent-child trios showed a significant preferential transmission of the 867Asp allele (McNemar chi(2)=5.81, df=1, P=0.016). Our results support the hypothesis that variation of the AE3 gene confers a common but small susceptibility effect to the etiology of a broad spectrum of IGE syndromes.