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Epilepsy
and GABA, their receptors, and the enzymes that regulate their mutations that lead to spontaneously occurring seizures in mice.
synthesis and degradation have been studied extensively in animal Examples include lethargic, slow-wave, stargazer, tottering, and
models of epilepsy and in human patients. In addition, many studies of weaver, which are models that exhibit both behavioral and
sodium channels have been conducted in epilepsy models as these electrographic seizure phenotypes. These monogenic mouse epilepsy
channel proteins play an important role in the generation and models are amenable to genetic dissection techniques, and the
propagation of neuronal action potentials. More recently, unbiased mutations underlying their phenotypes have been identified.
4–8
In each
genetic approaches have been used to identify other molecules whose case, the DNA mutation altered the structure and function of an
altered expression or function predisposes to seizures in animals encoded protein related to ion homeostasis. These findings add
and/or epilepsy in humans. support to the popular description of epilepsy as an ‘ion
channelopathy’ disease.
Genetics
Genetic influences contribute to the etiology of many epilepsy In contrast to monogenic mouse epilepsies, studies have also been
phenotypes in humans and animals. The influence of genetics on the performed on various inbred mouse strains in which robust
etiology of human epilepsy is supported by rigorous epidemiological differences in seizure susceptibility have been documented. The use
and genetic linkage data collected using classic family and twin study of chemoconvulsants, auditory stimuli, and direct electrical
designs. Several types of human (and animal) epilepsy cluster in stimulation has revealed that there is a large range of quantifiable
families with predictable inheritance patterns. These disorders are seizure susceptibilities among the many strains that have been
caused by mutation in a single gene (monogenic epilepsy), several of studied. Inheritance patterns in crosses between inbred strains
which have been identified.
2
However, monogenic forms of epilepsy are suggest that seizure susceptibility is a complex polygenic trait
rare, accounting for only 1–5% of all epilepsy cases. Common forms of resulting from variation at multiple genetic loci interacting with the
human epilepsy have complex inheritance patterns due to variation in environment. Work from the authors’ laboratories provides an
multiple genes interacting with environmental factors, which together example of how mouse models can be used to identify genetic
increase susceptibility to seizures and result in epilepsy. In an effort to determinants of seizure susceptibility. The approach is based on two
identify genetic influences on complex common forms of epilepsy, a common inbred strains of mice with extremely disparate
number of complementary experimental approaches have been susceptibility to experimental seizures: C57BL6/J (B6)—relatively
pursued in both animal models and human patient populations. This resistant—and DBA/2J (D2)—relatively susceptible. Application of a
article highlights some of the successful paradigms employed to quantitative trait locus (QTL) mapping strategy to these strains led to
identify genetic variation linked to or associated with seizure the nomination
9
and identification
10
of Kcnj10 genetic variation as a
susceptibility in animals and epilepsy in humans. major influence in the model. The Kcnj10 gene encodes an inward
rectifier potassium ion channel protein that transports potassium
Animal Models from the extracellular space into glial cells. Potassium is released
For many years, breeders of purebred dogs have known that genetic from neurons during action potentials and extracellular
influences play a major role in predisposition for epilepsy, as certain concentrations rise to particularly high levels during repetitive neural
breeds are at high risk and selective breeding successfully avoids activity. High extracellular potassium concentrations make neurons
seizure disorders in progeny derived from non-epileptic parents. hyper-excitable; however, Kir4.1-mediated potassium buffering
Molecular genetic studies are under way to identify these gene prevents this and allows maintenance of neuronal membrane
variations in canine breeds and once identified their homologs in excitability. Translation of the mouse studies into a human genetic
human patients can be studied in detail.
3
Other examples of animals association study involving over 400 epilepsy patients and 284
with documented spontaneous seizures likely caused by genetic controls revealed a mis-sense coding variation in KCNJ10 homolog
mutation include mice, rats, gerbils, baboons, and even fruit flies. (Arg271Cys) in which the Arg271 allele confers significant risk for the
While studies of all of these species have made important development of common forms of epilepsy including idiopathic
contributions, mice are the most widely used animal model for generalized epilepsy (IGE) and temporal lobe epilepsy (TLE).
11
In a
genetic epilepsy research. confirmatory study involving 550 IGE patients and 660 controls,
12
the
Arg271 allele was again revealed to increase epilepsy risk
The Mouse significantly. Taken together, these results comprise potentially
Mice are similar to humans with respect to physiology, anatomy, and important translational research—a unique success in translational
genetics. The generation and use of inbred mouse strains over the research involving mouse and human genetic studies of epilepsy that
past 100 years has made the mouse an ideal genetic organism and a has resulted in the identification of a novel target for antiepilepsy
valuable tool in the search for seizure-causing genes. Computer treatment development.
databases, specialized reagents, and careful phenotyping resources
that facilitate genetic studies in the mouse are unrivaled by resources Human Epilepsy
available for genetic studies on any other vertebrate species, Despite recent advances in the development of antiepileptic
including humans. The mouse genome is fully sequenced and the medications, clinical management of epilepsy is often complicated
opportunity to generate genetically modified mice through selective and adequate control of symptoms is difficult to maintain.
13
Moreover,
breeding, transgenesis, and knock-out/knock-in technology is readily many of the drugs currently used to treat epilepsy can have
available. Importantly, researchers have identified single gene deleterious side effects and precipitate serious drug–drug
64 US NEUROLOGY
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