Identification of Candidate Genes for Generalized Tonic–Clonic Seizures in Noda Epileptic Rat
- 445 Downloads
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 Gαi-interacting protein involved in GABAB receptor signaling pathway. Based on these findings, we conclude that Cckbr, St5, and Phf24 are strong candidate genes for GTCS in NER.
KeywordsCckbr Generalized tonic–clonic seizures Noda epileptic rat Phf24 St5
This study was supported in part by JSPS KAKENHI Grant Numbers JP12680810 to KK and JP20240042 to TS, and by Japan Epilepsy Research Foundation to YO. We are thankful to the National Bio Resource Project–Rat (http://www.anim.med.kyoto-u.ac.jp/NBR/) for providing NER/Kyo rats. We are grateful to C. Yamane, K. Kumafuji, and Z. Cui for technical assistance in animal breeding and care, and to H. Yamazoe for phenotyping of backcross progeny.
Compliance with ethical standards
Conflict of interest
Takashi Kuramoto, Birger Voigt, Satoshi Nakanishi, Kazuhiro Kitada, Tadashi Nakamura, Kaori Wakamatsu, Minako Yoshihara, Mikita Suyama, Risa Uemura, Miyuu Tanaka, Mitsuru Kuwamura, Saki Shimizu, Yukihiro Ohno, Masashi Sasa and Tadao Serikawa declare that they have no conflict of interest.
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All applicable international and institutional guidelines for the care and use of laboratory animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not describe any studies with human participants performed by any of the authors.
Supplementary Video 1. GTCS of NER. GTCS observed in 7-month-old female NERs (MP4 249030 KB)
Supplementary Video 2. GTCS of HER. GTCS observed in 6-month-old female HERs (MP4 78886 KB)
- Gaillard S, Lo Re L, Mantilleri A, Hepp R, Urien L, Malapert P, Alonso S, Deage M, Kambrun C, Landry M, Low SA, Alloui A, Lambolez B, Scherrer G, Le Feuvre Y, Bourinet E, Moqrich A (2014) GINIP, a Gαi-interacting protein, functions as a key modulator of peripheral GABAB receptor-mediated analgesia. Neuron 84(1):123–136CrossRefPubMedGoogle Scholar
- Liska F, Gosele C, Rivkin E, Tres L, Cardoso MC, Domaing P, Krejci E, Snajdr P, Lee-Kirsch MA, de Rooij DG, Kren V, Krenova D, Kierszenbaum AL, Hubner N (2009) Rat hd mutation reveals an essential role of centrobin in spermatid head shaping and assembly of the head-tail coupling apparatus. Biol Reprod 81(6):1196–1205CrossRefPubMedPubMedCentralGoogle Scholar
- McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20(9):1297–1303CrossRefPubMedPubMedCentralGoogle Scholar