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• W2121678733 abstract "Epilepsy is a common polygenic multifactorial disorder that involves complex interactions between genetic and environmental factors, and has multiple and highly variable phenotypic manifestations. Although genetics may not be considered as a factor in the development of all forms of epilepsy, many lines of evidence indicate that the genetic background of the host plays an important role in neuropathological sequelae (Goulon et al., 1985; DeLorenzo et al., 1995; Fountain and Lothman, 1995; Mathern et al., 1998; Mathern et al., 2002). In this postgenome era, the sequencing of the human and murine genomes offers an opportunity to accelerate the search for new pathological pathways. Progress has been made in the identification of epilepsy-modifying genes in both human studies and through the use of animal models. Based on epidemiological evidence, it is clear that a thorough understanding of the genetic determinants of status will provide important tools to improve the current preventative and therapeutical strategies and reduce the risks and the economical burden of this disorder. Identification of disease-causative loci for polygenic traits, such as status, in humans is confounded by several factors including genetic heterogeneity and the complex interactions of environmental and genetic factors. Although human studies have suggested that genetic factors contribute to seizure-induced cell death (Goulon et al., 1985; DeLorenzo et al., 1995; Fountain and Lothman, 1995; Mathern et al., 1998; Mathern et al., 2002; Shorvon, 2002), human genetic approaches are limited in the ability to undertake systematic investigations of the genetic pathways and pathological mechanisms involved in status. The use of inbred strains of mice for genetic analyses minimizes several of these factors. Among mice, there are no known inbred strains that spontaneously develop status. For this reason, researchers have used induced models of status in experiments involving genetic analyses. Animal models of status offer an opportunity to dissect the genetic basis of disease in a simplified genome and controlled environment with the aim of identifying new pathological pathways. To identify and disentangle the genetic factors underlying the risk for status, basically two approaches can be applied in the mouse: gene-driven and phenotype-driven. In the gene-driven (reverse genetic) approach, mutations that are produced by replacement of a gene of choice or transgenesis are used to determine the role of a particular gene within a specific system and serve as the starting point for analysis of the resulting phenotype. At present, gene function can be disrupted, attenuated, or enhanced in conditional and reversible fashion using a combination of gene targeting and transgenic approaches. It has become increasingly clear that a number of genes can modulate susceptibility to seizure-induced excitotoxic cell death (see Table 1), and much research has focused on identifying genes that may contribute to the pathogenic sequelae of neuronal damage. While mutation of a number of genes has suggested an important role in modulation of hippocampal neuronal injury following experimentally induced status, in a vast majority of these studies, it remains unclear if any putative neuroprotective or enhanced susceptibility effects are the result of gene manipulation or a modulation of seizure activity. To have analogous seizure patterns is vital, as studies have shown that variation in seizure duration, latency, and severity can alter the subsequent cell death (Sperk et al., 1985; Ferraro et al., 1995; Galanopoulou et al., 2002; Holmes, 2002). Thus, results from these studies suggest that any neuromodulatory effects observed are not solely the result of gene manipulation but rather the result of altered seizure sensitivity. In the phenotype-driven (forward genetics) approach, the phenotype of interest is the starting point of the study. Phenotype-driven approaches use genetic dissection (e.g., the identification and mapping of specific genes) to isolate mutants that affect a process of interest. Importantly, phenotype-driven approaches do not make any a priori assumptions about the relationship between the gene and phenotype and are therefore a relatively powerful route for discovering novel gene function and genetic pathways. In an attempt to perform a genetic dissection of susceptibility to seizure-induced cell damage through a linkage analysis approach, we created mouse hybrid populations from the crossbreeding of either seizure-induced damage-prone (FVB/NJ) and seizure-induced damage-resistant mice (C57BL/6J; Schauwecker, 2003). The purpose of linkage studies is to identify whether any part of the genome cosegregates with the occurrence of the pathological phenotype (i.e., onset of damage). In fact, in accordance with our original working hypothesis, several genomic regions were found to contribute directly to the cell damage phenotype, some of them by exerting a causative role, others by protecting animals from experiencing a significant amount of hippocampal damage (Schauwecker et al., 2004). To validate and further investigate a locus, a congenic strain can be created, which represents a genetic composite of the disease-susceptible strain and the disease-resistant strain. In particular, studies in our laboratory have been involved in the generation of mouse congenic lines carrying a seizure-induced cell damage quantitative trait locus (QTL) identified on mouse chromosome 18 of about 12 cM in size (Schauwecker et al., 2004), either in the seizure-induced cell damage prone configuration or vice versa (FVB.B6-Sicd1; as shown in Fig. 1). The phenotypic characterization of this line confirmed that gene(s) contained within this C57BL/6J-derived region could confer reduced susceptibility to seizure-induced cell death (Schauwecker et al., 2004; Lorenzana et al., 2007). Moreover, further dissection of this interval through the generation of interval-specific congenic lines (ISCLs), carrying smaller and smaller pieces of the original C57BL/6J locus, has enabled us to generate a fine saturated map of the region of interest (as shown in Fig. 1; Lorenzana et al., 2007). All of the ISCLs exhibited reduced cell death, associated with the “resistant” phenotype as compared to the parental FVB “susceptible” strain (see Fig. 1). Moreover, the contributory effect of genes appears to be independent from seizure-induction, thus confirming that the genes responsible for seizure susceptibility may be separate and distinct from those determining susceptibility to pathological injury. QTL mapping of the Sicd1 (seizure-induced cell death) location and refinement of the locus with congenic (FVB.B6-Sicd1) and interval-specific congenic (ISCLs1-4) mouse strains. Shown below the QTL locus is a schematic diagram of chromosome 18 in FVB.B6-Sicd1 congenic mice. Lightly shaded regions reflect genomic contribution from the FVB strain and darkly shaded regions reflect genomic contribution from the B6 strain. Shown below are four interval-specific congenic lines (ISCL1-ISCL4) that were developed and tested to attain higher-resolution mapping of Sicd1. Note that in both the homozygous FVB.B6-Sicd1 congenic and all ISCLs, susceptibility to seizure-induced excitotoxic cell death was reduced. Genetic dissection of complex traits is a difficult task due to the contribution of several genes, each one exerting a small effect on the final phenotype. By experimental approaches (gene- and phenotype-driven) and direct studies in humans (association studies), important results have been achieved for the comprehension of the genetic basis of common forms of seizure disorders. Thus, there can be much optimism that the genetic analysis of mouse models of status will lead to the identification of novel loci in mice and humans and a more profound understanding of the genetic etiology of this complex, multifactorial disorder. The identification of these loci and the study of the specific genes involved might offer the possibility of screens to predict susceptibility, which will assist physicians in identifying those patients who are at risk for developing injury. Moreover, the development of a new compilation of mouse mutants and a better understanding of the genetic basis of status will deliver opportunities to devise novel therapies as well as provide relevant models for preclinical testing." @default.
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• W2121678733 date "2007-10-30" @default.
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• W2121678733 title "Role of genetic influences in animal models of status" @default.
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• W2121678733 doi "https://doi.org/10.1111/j.1528-1167.2007.01340.x" @default.
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