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Behav Genet. 2017 Nov;47(6):609-619. doi: 10.1007/s10519-017-9870-2. Epub 2017 Sep 21.

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

Author information

1
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. tkuramot@anim.med.kyoto-u.ac.jp.
2
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
3
Division of Bioscience, Graduate School of Science, Hokkaido University, Sapporo, 060-0810, Japan.
4
Division of Molecular Science, Graduate School of Science and Technology, Gunma University, 1-5-1, Tenjin, Kiryu, Gunma, 376-8515, Japan.
5
Medical Institute of Bioregulation, Kyushu University, Maidashi, 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.
6
Laboratory of Veterinary Pathology, Osaka Prefecture University, Izumisano, Osaka, 598-8531, Japan.
7
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, 569-1094, Japan.
8
Nagisa Clinic, Hirakata, Osaka, 573-1183, Japan.
9
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. serikawa@anim.med.kyoto-u.ac.jp.
10
Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, 569-1094, Japan. serikawa@anim.med.kyoto-u.ac.jp.

Abstract

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.

KEYWORDS:

Cckbr; Generalized tonic–clonic seizures; Noda epileptic rat; Phf24; St5

PMID:
28936718
DOI:
10.1007/s10519-017-9870-2
[Indexed for MEDLINE]

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