Kuramoto Takashi, Voigt Birger, Nakanishi Satoshi, Kitada Kazuhiro, Nakamura Tadashi, Wakamatsu Kaori, Yoshihara Minako, Suyama Mikita, Uemura Risa, Tanaka Miyuu, Kuwamura Mitsuru, Shimizu Saki, Ohno Yukihiro, Sasa Masashi, Serikawa Tadao
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
Division of Bioscience, Graduate School of Science, Hokkaido University, Sapporo, 060-0810, Japan.
Behav Genet. 2017 Nov;47(6):609-619. doi: 10.1007/s10519-017-9870-2. Epub 2017 Sep 21.
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-interacting protein involved in GABA receptor signaling pathway. Based on these findings, we conclude that Cckbr, St5, and Phf24 are strong candidate genes for GTCS in NER.
野田癫痫大鼠（NER）表现出全身性强直阵挛性发作（GTCS）。一项遗传连锁分析确定了两个与GTCS相关的基因座，位于第1号染色体上的Ner1和位于第5号染色体上的Ner3。野生型Ner1和Ner3等位基因在双基因座同源系中组合时可抑制GTCS，但在单基因座同源系中存在时则不能。全局表达分析显示，位于Ner1内的胆囊收缩素B受体（Cckbr）和肿瘤抑制因子5（St5），以及位于Ner3内的PHD指蛋白24（Phf24）在NER中显著下调。从头BAC测序检测到NER基因组中Phf24基因内含子2中有一个内源性逆转录病毒序列插入，并且NER脑中几乎不存在PHF24蛋白。Phf24编码一种参与GABA受体信号通路的G相互作用蛋白。基于这些发现，我们得出结论，Cckbr、St5和Phf24是NER中GTCS的强有力候选基因。
