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.

Accession codes

Accessions

GenBank/EMBL/DDBJ

NCBI Reference Sequence

References

  1. 1

    Taylor, S.M. et al. Evaluations of Labrador retrievers with exercise induced collapse, including response to a standardized strenuous exercise protocol. J. Am. Anim. Hosp. Assn. (in the press).

  2. 2

    Taylor, S.M. in Blackwell's Five Minute Veterinary Consult: Canine and Feline 4th edn. Exercise induced weakness/collapse in Labrador Retrievers, 458–459 (Blackwell Publishing Professional, Ames, Iowa, 2007).

  3. 3

    Matwichuk, C.L., Taylor, S.M., Shmon, C.L., Kass, P.H. & Shelton, G.D. Changes in rectal temperature and hematologic, biochemical, blood gas, and acid-base values in healthy Labrador Retrievers before and after strenuous exercise. Am. J. Vet. Res. 60, 88–92 (1999).

  4. 4

    Taylor, S.M. et al. Exercise induced collapse of Labrador Retrievers: survey results and preliminary investigation of heritability. J. Am. Anim. Hosp. Assn. (in the press).

  5. 5

    Hungs, M. et al. Identification and functional analysis of mutations in the hypocretin (orexin) genes of narcoleptic canines. Genome Res. 11, 531–539 (2001).

  6. 6

    van De Sluis, B., Rothuizen, J., Pearson, P.L., van Oost, B.A. & Wijmenga, C. Identification of a new copper metabolism gene by positional cloning in a purebred dog population. Hum. Mol. Genet. 11, 165–173 (2002).

  7. 7

    Lingaas, F. et al. A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German shepherd dog. Hum. Mol. Genet. 12, 3043–3053 (2003).

  8. 8

    Lohi, H. et al. Expanded repeat in canine epilepsy. Science 307, 81 (2005).

  9. 9

    Karlsson, E. et al. Efficient mapping of mendelian traits in dogs through genome-wide association. Nat. Genet. 39, 1321–1328 (2007).

  10. 10

    Pennisi, E. The geneticist's best friend. Science 317, 1668–1671 (2007).

  11. 11

    Chen, X. et al. A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2. Neurogenetics 9, 41–49 (2008).

  12. 12

    Ramachandran, R. et al. The dynamin middle domain is critical for tetramerization and higher-order self-assembly. EMBO J. 26, 559–566 (2007).

  13. 13

    Noakes, P.G., Chin, D., Kim, S.S., Liang, S. & Phillips, W.D. Expression and localisation of dynamin and syntaxin during neural development and neuromuscular synapse formation. J. Comp. Neurol. 410, 531–540 (1999).

  14. 14

    Ferguson, S.M. et al. A selective activity-dependent requirement for dynamin 1 in synaptic vesicle endocytosis. Science 316, 570–574 (2007).

  15. 15

    Clark, S.G., Shurland, D.L., Meyerowitz, E.M., Bargmann, C.I. & van der Bliek, A.M. A dynamin GTPase mutation causes a rapid and reversible temperature-inducible locomotion defect in C. elegans. Proc. Natl. Acad. Sci. USA 94, 10438–10443 (1997).

  16. 16

    van der Bliek, A.M. & Meyerowitz, E.M. Dynamin-like protein encoded by the Drosophila shibire gene associated with vesicular traffic. Nature 351, 411–414 (1991).

  17. 17

    Grigliatti, T.A., Hall, T.L., Rosenbluth, R. & Suzuki, D. Temperature-sensitive mutations in Drosophila melanogaster. XIV. A selection of immobile adults. Mol. Gen. Genet. 120, 107–114 (1973).

  18. 18

    Grant, D., Unadkat, S., Katzen, A., Krishnan, K.S. & Ramaswami, M. Probable mechanisms underlying interallelic complementation and temperature sensitivity of mutations of the shibire locus of Drosophila melanogaster. Genetics 149, 1019–1030 (1998).

  19. 19

    Echaniz-Laguna, A. et al. Subtle central and peripheral nervous system abnormalities in a family with centronuclear myopathy and a novel dynamin 2 gene mutation. Neuromuscul. Disord. 17, 955–959 (2007).

  20. 20

    Züchner, S. et al. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease. Nat. Genet. 37, 289–294 (2005).

  21. 21

    Pele, M., Tiret, L., Kessier, J.L., Blot, S. & Panthier, J.J. SINE exonic insertion in the PTPLA gene leads to multiple splicing defects and segregates with the autosomal recessive centronuclear myopathy in dogs. Hum. Mol. Genet. 14, 1417–1427 (2005).

  22. 22

    Guyon, R. et al. A 1-Mb resolution radiation hybrid map of the canine genome. Proc. Natl. Acad. Sci. USA 100, 5296–5301 (2003).

  23. 23

    Breen, M. et al. An integrated 4249 marker FISH/RH map of the canine genome. BMC Genomics 5, 65 (2004).

  24. 24

    Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005).

  25. 25

    Cottingham, R.W. Jr, Idury, R.M. & Schäffer, A.A. Faster sequential genetic linkage computations. Am. J. Hum. Genet. 53, 252–263 (1993).

  26. 26

    Schäffer, A.A., Gupta, S.K., Shriram, K. & Cottingham, R.W. Jr. Avoiding recomputation in linkage analysis. Hum. Hered. 44, 225–237 (1994).

  27. 27

    Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. USA 81, 3443–3446 (1984).

  28. 28

    Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet. 11, 241–247 (1995).

  29. 29

    Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

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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.

Author information

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.

Correspondence to Edward E Patterson.

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Competing interests

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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