Neurological diseases are among the most common inherited diseases in humans. The primary cause of most neurological inherited diseases is not known, but many neurological mutations in mouse have been shown to have an equivalent human counterpart. Since mice are easier to analyze and can be bred at will, most murine neurological mutations have already been mapped to chromosomes. A molecular cloning of such murine mutations will be important to understand the basic functioning of the brain, and may help in defining the cause of some human neurological diseases. We propose here to characterize and clone the genes that when mutated cause the murine neurological mutations jittery and mocha. Mocha mice are characterized by inner ear defects, reduced bleeding times and a coat color defect, Notably, they sometimes show spike-wave discharges coupled to behavioral inactivity suggestive of absence seizures. Mocha homozygous mice also show a rhythmical, synchronous, high voltage activity on EEG, which is unique to this mutant and believed to be one of the first brain rhythm traits known to arise from a single gene defect. Jittery mice are characterized by progressively worsening dystonia and ataxia with tonic- clonic seizures, and die within one month after birth. These murine mutants map genetically close to each other and are located in a region of murine chromosome 10 that is homologous to a well- characterized region of human chromosome 21. The gene for Baltic progressive myoclonus epilepsy (Unverricht-Lundborg) maps to this region. This genetic proximity suggests that jittery may be a genetic murine model for Baltic progressive myoclonus epilepsy. We will approach mapping and ultimately cloning the genes involved in these two mutants by classical genetic methods, i.e. an intraspecific backcross with Mus musculus casjaneus, and molecular genetic techniques that take advantage of the large number of tools that have been developed by us and others for the study of human chromosome 21. Isolation of these genes will allow us to study and understand the primary cause of these specific neurological mutations, increase our understanding of brain function in general, and determine whether jittery is a murine model for Baltic progressive myoclonus epilepsy.
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