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

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; Tadao Serikawa

doi:10.1007/s10519-017-9870-2

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

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

Authors

Takashi Kuramoto¹, Birger Voigt², Satoshi Nakanishi², Kazuhiro Kitada³, Tadashi Nakamura⁴, Kaori Wakamatsu⁴, Minako Yoshihara⁵, Mikita Suyama⁵, Risa Uemura⁶, Miyuu Tanaka^{2

6}, Mitsuru Kuwamura⁶, Saki Shimizu⁷, Yukihiro Ohno⁷, Masashi Sasa⁸, Tadao Serikawa^{9

10}

Affiliations

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.

PMID: 28936718
DOI: 10.1007/s10519-017-9870-2

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 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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chromosomes, Mammalian / genetics
DNA-Binding Proteins / genetics
Disease Models, Animal
Electroencephalography / methods
Electroencephalography / veterinary
Epilepsy / genetics
Epilepsy, Tonic-Clonic / genetics*
Genetic Linkage / genetics
Genetic Loci / genetics
PHD Zinc Fingers / genetics
Rats
Rats, Wistar / genetics
Receptor, Cholecystokinin B / genetics*
Receptor, Cholecystokinin B / physiology
Seizures / genetics
Tumor Suppressor Proteins / genetics*

Substances

DNA-Binding Proteins
Receptor, Cholecystokinin B
Tumor Suppressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding