Mapping neurological and neuromuscular disease genes in dogs

The primary goal of this thesis was to define the genetic bases of canine Malignant Hyperthermia (MH), Exercise Induced Collapse (EIC), and epilepsy. MH in humans and pigs is a hypermetabolic reaction to certain anesthetics caused by a mutation in the skeletal muscle calcium release channel gene, RYR1. Genetic linkage analysis with markers near the RYR1 locus on CFA01 confirmed that MH susceptibility in a dog pedigree was linked to this locus. Partial RYR1 sequence analysis revealed a mutation changing amino acid 547 from a valine to an alanine that showed perfect cosegregation with the MH phenotype making dogs the third species for which an RYR1 mutation causes MH. Labrador Retrievers affected with EIC collapse after 5--15 minutes of intense exercise and are often confused as having a form of exercise induced MH. However, no EIC-affected dogs in a large pedigree in which EIC was segregating contained the RYR1 MH mutation. In addition, the locus was excluded as causative of EIC with CFA01 markers and we conclude that EIC is likely a novel canine disorder. Epilepsy in the Vizsla breed is characterized by primary recurrent seizures. A full genome scan approach was used to identify a locus linked to epilepsy in Vizsla dogs. Six loci on different chromosomes have been identified with potential linkage to epilepsy. Loci on CFA01 and CFA33 have significant linkage in a two-locus model for the disease. Lastly, 2000 brain Expressed Sequence Tags (ESTs) were identified and one hundred were assigned to the canine radiation hybrid (RH) map. This effort will help in positional cloning once loci are identified by genome scans, and identified several regions of previously unknown synteny between the human and dog genomes. Our investigations show that markers from the canine map can be used successfully in genome scans to identify loci causing canine diseases and that there is great potential for genes causing epilepsy and EIC to be identified in the populations already acquired. Such studies will be very important for improving the health and well being of dogs and will serve to identify valuable models for human conditions.