Summary.   Exercise‑induced collapse (EIC) is a recently recognized disorder of increasing significance in Labrador Retrievers, especially those dogs used for hunting and field trials. Dogs affected with EIC develop ataxia, incoordination and life-threatening collapse after just five to fifteen minutes of field exercise and cannot participate in many types of strenuous activities.  The condition can also unknowingly exist in dogs that are not routinely participating in such activity.  We have now shown that the disorder clearly runs in pedigrees and our clinical and pathological studies also indicate that no strong correlations likely exist between EIC and known disorders in other species.  Multi-generation pedigrees have been identified with which to perform a genome scan to map the chromosomal locus of the EIC gene with microsatellite DNA markers.  As a result, we have recently identified a chromosomal locus for an EIC gene and hope to identify an associated DNA mutation soon.  Successful completion of this project will provide breeders and veterinarians with a non-invasive test for definitive diagnosis, and a selection method for designing matings that will not produce affected dogs.

Genetic Basis of EIC.  All of the EIC dogs could be assembled into one very large kindred, indicating a familial basis for the condition. The pedigrees show that EIC-affected dogs of both sexes can be produced from the mating of apparently unaffected parents.  This is characteristic of an autosomal recessive disorder, although a dominant disorder with partial penetrance, or even a polygenic disorder cannot be excluded at this time because of ascertainment bias and incomplete litter collection.

Exclusion of the Malignant Hyperthermia (RYR1) gene.  Veterinarians and the public often confuse EIC with a rare condition known as malignant hyperthermia (MH), which is a hypermetabolic syndrome typically initiated by halogenated anesthetics, although examples of MH initiated by stress and exercise have been reported. We examined the known RYR1/MH locus on canine chromosome 1 for association with EIC in our large EIC pedigrees.  The results clearly indicated that the RYR1 gene can be excluded from causing EIC, and that EIC is not a classic form of MH.

Whole genome scan for linkage of DNA markers to EIC.   In the past 4 months we have identified a set of DNA markers on one of the canine chromosomes that have demonstrated significant linkage to EIC in the pedigrees.  This means that the gene that causes EIC is in the vicinity of these DNA markers on this chromosome.  This chromosomal segment has a number of genes readily identified from the canine and corresponding human DNA sequencing projects that participate in muscle and nerve function, that if defective, could conceivably cause clinical signs like those observed in EIC.

Plans for next 6 months.  The region of the canine chromosome that contains the EIC gene is in a gene-dense region of the chromosome in which there are several plausible candidate genes.  Therefore it will be necessary to further fine map the region with additional DNA markers and additional control and affected dogs to enable the selection of positional candidate genes for mutation detection.  To assist us in this fine mapping and exclusion effort we will include several non-Labrador Retriever samples with diagnoses of apparent EIC to see if inclusion of this related breed group helps narrow time the region of shared haplotypes for candidate gene selection.  Soon we will select candidate genes from the region for sequencing and DNA sequence polymorphism detection that will hopefully identify a mutation.

For related articles see June 2000 Case of  the Month and July 2001 Special Feature.