Labrador retrievers are the most common dog breed in the world, with over 200,000 new kennel club registrations per year. The syndrome of exercise-induced collapse (EIC) in this breed is manifested by muscle weakness, incoordination and life-threatening collapse after intense exercise. Using a genome-wide microsatellite marker scan for linkage in pedigrees, we mapped the EIC locus to canine chromosome 9. We then used SNP association and haplotype analysis to fine map the locus, and identified a mutation in the dynamin 1 gene (DNM1) that causes an R256L substitution in a highly conserved region of the protein. This first documented mammalian DNM1 mutation is present at a high frequency in the breed and is a compelling candidate causal mutation for EIC, as the dynamin 1 protein has an essential role in neurotransmission and synaptic vesicle endocytosis.
Bibliographical noteFunding Information:
We acknowledge the assistance of M. McCue and K. Matchett in manuscript preparation, S. Dalsen in figure preparation and C. Wade in SNP selection and analysis. This work was funded in part by grants from the Morris Animal Foundation to J.R.M., E.E.P. and S.M.T. (D01CA-021), and American Kennel Club Canine Health Foundation to J.R.M. and E.E.P. (#352). The contents of this publication are solely those of the authors and do not necessarily reflect the views of the Canine Health Foundation. This work is dedicated to the memory of Monica C. Roberts, who was a major contributor to the initiation of these studies.