Identification of Candidate Genes for Generalized Tonic–Clonic Seizures in Noda Epileptic Rat

The Noda epileptic rat (NER) exhibits generalized tonic–clonic seizures (GTCS). A genetic linkage analysis identified two GTCS-associated loci, Ner1 on Chr 1 and Ner3 on Chr 5. The wild-type Ner1 and Ner3 alleles suppressed GTCS when combined in double-locus congenic lines, but not when present in single-locus congenic lines. Global expression analysis revealed that cholecystokinin B receptor ( Cckbr ) and suppressor of tumorigenicity 5 ( St5 ), which map within Ner1 , and PHD finger protein 24 ( Phf24 ), which maps within Ner3 , were significantly downregulated in NER. De novo BAC sequencing detected an insertion of an endogenous retrovirus sequence in intron 2 of the Phf24 gene in the NER genome, and PHF24 protein was almost absent in the NER brain. Phf24 encodes a G αi -interacting protein involved in GABA B receptor signaling pathway. Based on these findings, we conclude that Cckbr, St5 , and Phf24 are strong candidate genes for GTCS in NER.