A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse

Abstract

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.

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Figure 1: CFA9 SNP association analysis.
Figure 2: SNP haplotypes and genes from the region of CFA9 genetically linked to EIC.
Figure 3: Dynamin amino acid sequence homologies and substitutions.

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Accessions

GenBank/EMBL/DDBJ

NCBI Reference Sequence

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Acknowledgements

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.

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S.M.T., E.E.P., J.R.M. and G.D.S. were responsible for the project's conception and initiation. S.M.T., G.D.S. and E.E.P. developed the phenotypic criteria. S.M.T., K.M.M., G.D.S. and E.E.P. recruited dogs into the study. K.M.M., A.V.T. and E.E.P. performed the microsatellite genotyping and linkage analysis. K.M.M., E.E.P., K.J.E. and J.R.M. were responsible for the SNP association and haplotype analysis. K.M.M. and J.R.M. performed and analyzed the DNA sequencing. J.R.M., E.E.P. and S.M.T. were responsible for overall project oversight. E.E.P. and J.R.M. co-wrote the manuscript, which was edited by all co-authors.

Corresponding author

Correspondence to Edward E Patterson.

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Four of the authors (E.E.P., K.M.M., S.M.T. and J.R.M.) have submitted a patent application entitled “Method of Detecting Canine Exercise-Induced Collapse”, and they will receive a portion of the royalties from genetic testing.

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Supplementary Tables 1–6, Supplementary Figures 1 and 2 (PDF 299 kb)

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Patterson, E., Minor, K., Tchernatynskaia, A. et al. A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse. Nat Genet 40, 1235–1239 (2008). https://doi.org/10.1038/ng.224

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