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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurological mutant mouse strain E1 is a model for complex partial seizures in humans. The inheritance of epileptic seizures with seven conventional chromosomal markers and over 60 endogenous proviral markers was studied by means of back-crosses of E1 with two seizure-resistant strains, DBA/2J and ABP/LeJ. The major gene responsible for this epileptic phenotype (El-1) was localized to a region distal with respect to the centromere on chromosome 9. At least one other gene, El-2, linked to proviral markers on chromosome 2, also influences the seizure phenotype. In addition, a potential modifier of seizures was detected in the DBA/2J background. The location of El-1 on distal chromosome 9 may allow identification of an epilepsy candidate gene in humans on the basis of conserved synteny with human chromosome 3.
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PMID:Genes for epilepsy mapped in the mouse. 187 1

The recombinant inbred mouse strain, SWXL-4, exhibits tonic-clonic and generalized seizures similar to the commonest epilepsies in humans. In SWXL-4 animals, seizures are observed following routine handling at about 80 days of age and may be induced as early as 55 days by rhythmic gentle tossing. Seizures are accompanied by rapid, bilateral high frequency spike cortical discharges and followed by a quiescent post-ictal phase. Immunohistochemistry of the immediate early gene products c-Fos and c-Jun revealed abnormal activation within cortical and limbic structures. The seizure phenotype of SWXL-4 can be explained and replicated fully by the inheritance of susceptibility alleles from its progenitor strains, SWR/J and C57L/J. Outcrosses of SWXL-4 with most other common inbred strains result in F1 hybrids that have seizure at least as frequently as SWXL-4 itself. Quantitative trait locus mapping reveals a seizure frequency determinant, Szf1, near the pink-eyed dilution locus on chromosome 7, accounting for up to 32% of the genetic variance in an F2 intercross between SWXL-4 and the linkage testing strain ABP/Le. These studies demonstrate that common strains of mice such as SWR and C57L contain latent epilepsy susceptibility alleles. Although the inheritance of susceptibility may be complex, these results imply that a number of potentially important and practical, noninvasive models for this disorder can be constructed and studied in crosses between common mouse strains.
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PMID:Genetic epilepsy model derived from common inbred mouse strains. 782 29

Congenic mouse strains made by transferring epilepsy predisposing alleles El1, El2, and El3 from the EL/Suz strain to the ABP/Le recipient were tested for seizure frequency following gentle rhythmic stimulation. Mice homozygous for El2, but not El1 or El3, experienced seizures much more frequently than ABP controls, while respective El1 homozygotes and El2 heterozygotes had only a modest increase over ABP, and El3 homozygotes showed no increase. Association between marker genotypes and seizure frequency in small intra-strain crosses showed that the phenotypic effects of El2 map to the selected interval, and that segregation of El2 accounts for virtually all genetic effects. However, in separating El2 from other EL susceptibility alleles, the seizure frequency phenotype was weaker and less heritable than in crosses between parental strains. These results confirm El2 as an important QTL and show that it has significant phenotypic effects in the absence of other EL-derived alleles, including El1. In addition, the present localization of El2 on Chr 2 suggests several potential candidate genes for El2, including the beta subunit of phospholipase-C. The approach to dissecting complex traits by making congenic strains for individual QTL is discussed.
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PMID:Congenic strains reveal effects of the epilepsy quantitative trait locus, El2, separate from other El loci. 874 21

EL/Suz (EL) mice experience recurrent seizures that are similar to common partial complex epilepsy in humans. In the mice, seizures occur naturally at 90-100 days of age, but can be induced in younger mice and analyzed as a semi-quantitative trait after gentle rhythmic stimulation. A previous genetic mapping study of EL backcrosses to the strains ABP/LeJ or DBA/2J showed two quantitative trait loci (QTL) with large effects on seizure frequency (El1, Chr 9; El2, Chr 2) and implied the existence of other QTL with lesser effects. To further the understanding of EL-derived seizure alleles, we examined intercross progeny of EL and the strains ABP/LeJ and DDY/Jcl, and also a backcross of (EL x DDY)F1 hybrids to DDY. A new large-effect seizure frequency QTL was found (El5, Chr 14), a more minor QTL confirmed (El3, Chr 10), and two additional QTL proposed (El4, Chr 9; El6, Chr 11). The serotonin receptor gene, Htr2a, maps near and is a candidate for El5, and linkages of other serotonin receptor genes to seizure frequency QTL are noted. In addition, a strong gender effect was revealed, and epistasis was found between Chr 9 and Chr 14 markers. Despite this progress, however, our results revealed a more complex determinism of epilepsy in EL mice than previously described. In particular, no single El locus or pair was essential for frequent seizures, as QTL with large effects, such as El5, El2, and El1, were highly dependent on genetic context. Our studies highlight the importance of gene interaction in some complex mammalian traits defined by natural variation.
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PMID:New seizure frequency QTL and the complex genetics of epilepsy in EL mice. 874 20

Analysis of beta-CCM induced seizures in three inbred strains of mice, ABP/Le, C57BL/6J and C57BL/6ByJ, and their F1s and F2s progeny, allowed identification of a putative seizure susceptibility controlling locus on chromosome 9 near the short-ear locus. The involvement of a gene in the medial segment of this chromosome in both seizure activity and GABA-controlled behaviour is discussed.
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PMID:Mouse chromosome 9 involvement in beta-CCM-induced seizures. 893 Sep 94

The linkage-testing strain of ABP/Le mice carries six mutations which express in easily identifiable phenotypes. By crossing this strain with a traditional inbred strain (C57BL/6ByJ) which is the 'wild type' for the mutated ABP/Le loci, we produced Mendelian populations, intercrosses and backcrosses so as to estimate whether the sensitivity to methyl beta-carboline-3-carboxylate (beta-CCM), a benzodiazepine receptor inverse agonist, and anxiety-related behaviour could be related to a common genetically determined substrate. We have shown that one locus on chromosome 9 is associated with beta-CCM-induced seizures and three loci on chromosomes 4, 7 and 9 are associated with anxiogenic processes. Analysis of [3H]flumazenil binding suggested a possible involvement of a Bmax decrease in both beta-CCM-induced seizures and anxiogenic processes. The putative common genetic regulation of both mechanisms is discussed.
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PMID:Convulsive effects of a benzodiazepine receptor inverse agonist: are they related to anxiogenic processes? 921 97

The epileptic EL mouse has been studied extensively as a genetic model for idiopathic complex partial seizures in humans. The seizures in EL mice occur during routine handling at approximately 90 days of age, but can be induced at younger ages (50 days) by repeated rhythmic vestibular stimulation, e.g., tossing. Six seizure frequency quantitative trait loci (QTLs), El1-El6, were previously mapped in crosses between EL and non-epileptic strains using mechanical tossing procedures beginning at 30 days of age. The presence of these seizure frequency QTLs depended upon genetic background and the type of cross. Here we confirm Chromosome 2 and 9 QTLs in a backcross to the seizure-resistant ABP/LeJ strain with mice tested beginning at 200 days of age. However, the mapping of epilepsy genes was influenced by the seizure testing procedure, i.e., repeated tossing. The maximum Z-score for El1 (Chromosome 9) was 3.7 after 6 tests, but decreased to 2.4 after 15 tests. In contrast, the maximum Z-score for El2 (Chromosome 2) was 2.0 after 6 tests, but increased to 3.9 after 15 tests. In addition to nonallelic interactions (epistasis), our findings indicate that the genetic complexity of tossing-induced seizure susceptibility in EL mice also arises from genotype-environmental interactions involving the seizure test, seizure history, and age.
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PMID:Environmental influences on epilepsy gene mapping in EL mice. 1019 58

The EL mouse strain provides a polygenic model for epilepsy. Previous mapping experiments between EL and nonepileptic ABP mice identified, and a congenic strain confirmed, a quantitative trait locus (QTL), El2, which lowered the threshold to seizures induced by gentle rhythmic tossing. To narrow the map interval further we used a nested strategy to analyze a series of recombinants derived from the congenic strain. The recombinant strains revealed a complex pattern of inheritance, with at least two independent regions of Chromosome 2 necessary for rhythmic tossing seizures and additional regions associated with unusual gender effects. Similar results obtained using a completely independent paradigm, pentylenetetrazole-induced tonic-clonic seizures, exclude the possibility that the genetic complexity was a unique property of the testing assay. Thus, although conventional QTL mapping efforts detected and appeared to confirm a trait locus with effects large enough for fine-structure mapping, subsequent dissection revealed multiple loci. Although at least one of these loci was mapped to a 1-cM interval, its individual effect is small, perhaps approaching the practical limits for further study. Our results in the EL mouse may be prophetic for similar assaults on other polygenic, composite neurological behaviors which vary among inbred strains, begging the consideration of alternative strategies toward gene identification in these models.
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PMID:A major effect QTL determined by multiple genes in epileptic EL mice. 1064 48

The SWXL-4 recombinant inbred mouse strain is unusually sensitive to recurrent tonic-clonic seizures upon routine handling and to seizures induced by chemoconvulsants. In a conventional intercross with the ABP/Le strain, we previously mapped a SWXL-4-derived quantitative trait locus called Szf1 (seizure frequency 1) to Chromosome 7. In the present study, we confirm the existence of Szf1 in both an independent cross and a congenic strain. However, derivative congenic recombinant strains show that an interaction between at least two genes on Chromosome 7-each of which has a very small effect on its own-account for Szf1.
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PMID:Multiple seizure susceptibility genes on chromosome 7 in SWXL-4 congenic mouse strains. 1108 62

Gene identification has progressed rapidly for monogenic epilepsies, but complex gene-environmental interactions have hindered progress in gene identification for multifactorial epilepsies. We analyzed the role of environmental risk factors in the inheritance of multifactorial idiopathic generalized epilepsy in the EL mouse. Seizure susceptibility was evaluated in the EL (E) and seizure-resistant ABP/LeJ (A) parental mouse strains and in their AEF1 and AEF2 hybrid offspring using a handling-induced seizure test. The seizure test was administered in three environments (environments I, II and III) that differed with respect to the number of seizure tests administered (one test or four tests) and the age of the mice when tested (young or old). The inheritance of seizure susceptibility appeared dominant after repetitive seizure testing in young or old mice, but recessive after a single test in old mice. Heritability was high (0.67-0.77) in each environment. Significant quantitative trait loci (QTL) that were associated with environments I and III (repetitive testing) were found on chromosomes 2 and 9 and colocalized with previously mapped El2 and El4, respectively. The El2 QTL found in environment I associated only with female susceptibility. A novel QTL, El-N, for age-dependent predisposition to seizures was found on proximal chromosome 9 only in environment II. The findings indicate that environmental risk factors determine the genetic architecture of seizure susceptibility in EL mice and suggest that QTL for complex epilepsies should be defined in terms of the environment in which they are expressed.
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PMID:Genetic and environmental interactions determine seizure susceptibility in epileptic EL mice. 1701 98


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