The goal of this project is clone and study the canine narcolepsy gene. Canine narcolepsy is known to be transmitted as a single autosomal receive genes with full penetrance, canarc-1. The deficient mutant gene has been mapped with a 4 Mb genomic segment of CFA 12. This segment is flanked by crossovers in Doberman backcrosses. With the use of the recently build canine genomic Bacterial Artificial Chromosome (BAC) library, the entire physical region ha snow been entirely isolated. We have also recently identified two narcoleptic pedigrees suggesting a most likely location of canarc-1 within a 800 kb sub-segment of the larger 4 Mb region. The overall LOD score in this subregion is 32.1 at 0% recombination. Selected animal crosses will be performed to confirm this latest mapping data. One of the highest priorities of this project will be to complete the construction of a sequence-ready contig map of the region. The construction of the contig will use Sequence-tagged site (STS) typing and BAC clone fingerprinting. We will also proceed with candidate gene isolation using exon trapping, direct selection and shot gun sequence the region, starting with the 800kb segment and extending work if needed. We feel confident the canine narcolepsy gene will be isolated within the next funding period. As canarc-1 is the only known single gene sleep mutation, we believe the isolation and study of the mutation will not only shed new light on the pathophysiology of narcolepsy but may also bring novel information regarding sleep control in general.
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| de Lecea, Luis (2015) Optogenetic control of hypocretin (orexin) neurons and arousal circuits. Curr Top Behav Neurosci 25:367-78 |
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