Chromosomal Mapping of Genes for Epilepsy in NER: A Rat Strain with Tonic‐Clonic Seizures

Maihara, Toshiro; Noda, Atsushi; Yamazoe, Hirotake; Voigt, Birger; Kitada, Kazuhiro; Serikawa, Tadao

doi:10.1111/j.1528-1157.2000.tb00276.x

Cited by 17 publications

(8 citation statements)

References 33 publications

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“…Genes that influence a mutant phenotype can be identified systematically by evaluating the seizure phenotype on different background strains. Several strain‐dependent seizure susceptibility loci and genes have been identified (Chaix et al 2007; Ferraro et al 2001, 2004, 2007a,b, 2010, 2011; Frankel et al 1995; Gershenfeld et al 1999; Legare et al 2000; Maihara et al 2000; Winawer et al 2011).…”

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confidence: 99%

Confirmation of an epilepsy modifier locus on mouse chromosome 11 and candidate gene analysis by RNA‐Seq

Hawkins

Kearney

2012

Genes Brain and Behavior

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Epilepsy is a neurological disorder affecting approximately 1% of the worldwide population. Mutations in voltage-gated sodium channels have been identified in several monogenic epilepsy syndromes. Over 800 mutations have been identified in the voltage-gated sodium channel genes SCN1A and SCN2A in human epilepsies, including Genetic Epilepsy with Febrile Seizures Plus (GEFS+) and Dravet Syndrome. In GEFS+ families, affected members with the same mutation often display variability in clinical severity of the disease. This suggests that additional genes modify the effect of the primary mutation, resulting in the variable clinical presentation. The Scn2aQ54 transgenic mouse model has an epilepsy phenotype that varies depending on the genetic strain background. Scn2aQ54 mice congenic on the C57BL/6J strain exhibit delayed seizure onset and improved survival compared to (C57BL/6J × SJL/J)F1.Q54 mice. Two modifier loci of Scn2aQ54 seizure susceptibility were mapped and designated Moe1 (modifier of epilepsy) on chromosome 11 and Moe2 on chromosome 19. To confirm Moe1 and refine its position, we generated interval specific congenic (ISC) lines carrying C57BL/6J-derived chromosome 11 alleles on the SJL/J strain and refined the map position to 89–104 Mb. We then used RNA-Seq for candidate analysis in the modifier region. C57BL/6J and SJL/J male and female brain RNAs were sequenced, revealing numerous significant transcriptome differences and coding SNPs. Additional consideration of gene function and expression suggested several strong candidate modifier genes, including two voltage-gated calcium channel subunits, Cacna1g and Cacnb1, and the PAR bZIP transcription factor, Hlf.

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confidence: 99%

Confirmation of an epilepsy modifier locus on mouse chromosome 11 and candidate gene analysis by RNA‐Seq

Hawkins

Kearney

2012

Genes Brain and Behavior

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“…The seizures are inhibited by conventional antiepileptics such as diazepam, valproate, phenobarbital, and carbamazepine, but rarely inhibited by phenytoin, zonisamide, and ethosuximide (12). The genes responsible for the seizures of NER, designated Ner1 and Ner2, were found to be located on chromosomes 1 and 3, respectively (13). In addition to these findings, we have recently found that hippocampal CA3 neurons of young NER show a long-lasting depolarization shift accompanied by repetitive firings following a single stimulation of the mossy fibers, before spontaneous seizures appear manifestly (8).…”

Section: Discussionmentioning

confidence: 77%

Involvement of Ca2+ Channels in Abnormal Excitability of Hippocampal CA3 Pyramidal Cells in Noda Epileptic Rats

et al. 2003

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Noda epileptic rat (NER) is a mutant rat, which spontaneously exhibits a tonic-clonic convulsion from 14 weeks of age. An intracellular recording study was performed to elucidate the abnormal excitability of NER hippocampal CA3 neurons. The recorded neurons were classified into two groups, group A and B neurons, according to the responses to a single stimulation of mossy fibers. In group A neurons, a stimulus elicited a long-lasting depolarization shift accompanying repetitive firings followed by after-hyperpolarization. In group B neurons, the same stimulus elicited a single spike without a long-lasting depolarization shift. Bath application of 1 mM Cd(2+), a nonselective Ca(2+) channel blocker, completely inhibited the abnormal excitation in group A neurons. We further examined the character of Ca(2+) spikes in NER CA3 neurons. Ca(2+) spikes were completely blocked by 10 microM Cd(2+) in group A neurons, but not in either group B or control neurons, suggesting that Ca(2+) channels in NER group A neurons have the hypersensitivity to Cd(2+). Analysis using subtype specific blockers of Ca(2+) channel raised the possible involvement of T-type Ca(2+) channels. These results suggest that Ca(2+) channel dysfunction is involved in the abnormal excitability of CA3 pyramidal neurons and pathogenesis of epilepsy in NER.

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“…Since the initial efforts on diabetes, QTL have been located for a wide variety of phenotypes (Rikke and Johnson 1998), including atherosclerosis (Hyman et al 1994;Ko et al 2001;Mu et al 1999;Paigen et al 1987a,b;Pitman et al 1998;Purcell et al 2001); epilepsy (Frankel et al 1995a,b;Gershenfeld et al 1999;Legare et al 2000;Maihara et al 2000;Miner and Marley 1995); obesity (Brockmann et al 2000;Horvat et al 2000;Schalling et al 1999;Taylor et al 1999Taylor et al , 2001; asthma (De Sanctis and Drazen 1997;De Sanctis et al 1999;Dwyer-Nield et al 2000;Ewart et al 2000;Nicolaides et al 1997;Symula et al 1999); lupus (Gu et al 1998;Santiago et al 1998); osteoporosis (Benes et al 2000;Hosoi 2001;Shimizu et al 1999); hypertension (Sugiyama et al 2001a,b); and a variety of cancers including lung (Festing et al 1994Lin et al 1998), skin (Nagase et al 1996(Nagase et al , 1999(Nagase et al , 2001, and colon (Gould and Dove 1998;MacPhee et al 1995).…”

Section: Natural Polymorphismsmentioning

confidence: 98%

Understanding the Human Condition: Experimental Strategies in Mammalian Genetics

Paigen

2002

ILAR Journal

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Mice have become the mammalian model of choice for the application of genetics in biomedical research due to the evolutionary conservation of physiological systems and their attendant pathologies among all mammals as well as the exceptional power of genetic research technologies in the species. Beginning from aberrant phenotypes, a large number of mouse mutants and natural polymorphisms have been cloned, providing much information about the molecular basis of physiological processes. Additionally, the variable expression of these mutations in different inbred strain backgrounds has demonstrated the importance of modifier genes, which are also susceptible to cloning. Research efforts are keeping pace with these developments. In the area of gene discovery, large, government-funded mutagenesis programs now exist, and as a matter of great practical importance, recent evidence suggests that the same genes may be involved in the natural polymorphisms affecting disease in mice and humans. In parallel, dramatic advances are also being made in our ability to measure physiological processes in mice, and the advent of expression profiling promises revolutionary advances in understanding phenotype at the molecular level. Gene-driven approaches have relied on engineering the mouse genome, including adding, subtracting, and replacing genes and, most recently, the ability to control gene activity reversibly. Together, these multiple advances in our technical abilities have created extraordinary opportunities for future discovery.

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Chromosomal Mapping of Genes for Epilepsy in NER: A Rat Strain with Tonic‐Clonic Seizures

Cited by 17 publications

References 33 publications

Confirmation of an epilepsy modifier locus on mouse chromosome 11 and candidate gene analysis by RNA‐Seq

Confirmation of an epilepsy modifier locus on mouse chromosome 11 and candidate gene analysis by RNA‐Seq

Involvement of Ca2+ Channels in Abnormal Excitability of Hippocampal CA3 Pyramidal Cells in Noda Epileptic Rats

Understanding the Human Condition: Experimental Strategies in Mammalian Genetics

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