A splice site mutation in a gene encoding for PDK4, a mitochondrial protein, is associated with the development of dilated cardiomyopathy in the Doberman pinscher

Hum Genet. 2012 Aug;131(8):1319-25. doi: 10.1007/s00439-012-1158-2. Epub 2012 Mar 25.


Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genome-wide association analysis identified an area of statistical significance on canine chromosome 14 (p(raw) = 9.999e-05 corrected for genome-wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190-23,781,919 (p = 0.001) and DNA sequencing identified a 16-base pair deletion in the 5' donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs (p < 0.0001). Electron microscopy of myocardium from affected dogs demonstrated disorganization of the Z line, mild to moderate T tubule and sarcoplasmic reticulum dilation, marked pleomorphic mitochondrial alterations with megamitochondria, scattered mitochondria with whorling and vacuolization and mild aggregates of lipofuscin granules. In conclusion, we report the identification of a splice site deletion in the PDK4 gene that is associated with the development of familial dilated cardiomyopathy in the Doberman pinscher dog.

MeSH terms

  • Animals
  • Blotting, Western
  • Cardiomyopathy, Dilated / genetics
  • Cardiomyopathy, Dilated / veterinary*
  • Chromosome Mapping / veterinary
  • Dog Diseases / genetics*
  • Dogs
  • Genome-Wide Association Study
  • Microscopy, Electron
  • Mutation*
  • Myocardium / ultrastructure
  • Protein Kinases / genetics*
  • RNA Splicing*
  • Real-Time Polymerase Chain Reaction


  • Protein Kinases
  • pyruvate dehydrogenase kinase 4