Skip to main content
SpringerLink
Log in

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

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Arbustini E, Diegoli M, Fasani R, Grasso M, Morbini P, Banchieri N, Bellini O, DalBello B, Pilotto A, Magrini G, Campana C, Fortina P, Gavazzi A, Narula J, Vigano M (1998) Mitochondrial DNA mutations and mitochondrial abnormalities in dilated cardiomyopathy. Am J Path 153:1501–1510

    Article  PubMed  CAS  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2004) HalpoviewL analysis and visualization of LD and haploview maps. Bioinformatics 21:263–265

    Article  PubMed  Google Scholar 

  • Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM (1998) Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenases complex. Biochem J 329:191–196

    PubMed  CAS  Google Scholar 

  • Burkett EL, Hershberger RE (2005) Clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 45:969–981

    Article  PubMed  CAS  Google Scholar 

  • Butcher LM, Davis OSP, Craig IW, Plomin R (2008) Genome-wide quantitative trait locus association scan of general cognitive ability using pooled DNA and 500 K single nucleotide polymorphism microarrays. Genes Brain Behav 7:435–446

    Article  PubMed  CAS  Google Scholar 

  • Dukes-McEwan J, Borgarelli M, Tidholm A, Vollmar AC, Haggstrom J (2003) Proposed guidelines for the diagnosis of canine idiopathic dilated cardiomyopathy. J Vet Cardiol 5:7–19

    Article  PubMed  Google Scholar 

  • Eng L, Coutinho G, Nahas S, Yeo G, Tanouye R, Babaei M, Dork T, Burge C, Gatti RA (2004) Nonclassical splicing mutations in the coding and noncoding regions of the ATM gene: Maximum entropy estimates of splice junction strengths. Hum Mut 23:67–76

    Article  PubMed  CAS  Google Scholar 

  • Guenthard J, Wyler F, Fowler B, Baumgartner R (1995) Cardiomyopathy in respiratory chain disorders. Arch Dis Child 72:223–226

    Article  PubMed  CAS  Google Scholar 

  • Hershberger RE, Cowan J, Morales A, Siegfried JD (2009) Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated hypertrophic and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Heart Fail 2:253–261

    Article  PubMed  Google Scholar 

  • Hershberger RE, Morales A, Siegfried JD (2010) Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genet Med 12:655–667

    Article  PubMed  CAS  Google Scholar 

  • Hoppel CL, Tandler B, Fujioka H, Riva A (2009) Dynamic organization of mitochondria in human heart and in myocardial disease. Int J Biochem Cell Biol 41:1949–1956

    Article  PubMed  CAS  Google Scholar 

  • Karlsson EK, Baranowska I, Wade CM, Salmon Hillbertz NH, Zody MC, Anderson N, Biagi TM, Patterson N, Pielberg GR et al (2007) Efficient mapping of Mendelian traits in dogs through genome-wide association. Nat Genet 39:1321–1328

    Article  PubMed  CAS  Google Scholar 

  • Lei B, Lionetti V, Young ME, Chandler MP, d’Agostino C, Kang E, Altarejos M, Matsuo K, Hintze TH, Stanley WC, Recchia FA (2011) Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure. J Mol and Cell Cardiol 36:567–576

    Article  Google Scholar 

  • Lopaschuk GD, Ussher JR, Folmes CDL, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90:207–258

    Article  PubMed  CAS  Google Scholar 

  • Lopes R, Solter PF, Sisson D, Oyama MA, Prosek R (2006) Characterization of canine mitochondrial protein expression in natural and induced forms of idiopathic dilated cardiomyopathy. Am J Vet Res 67:963–970

    Article  PubMed  CAS  Google Scholar 

  • Mary J, Chetboul V, Sampedrano CC, Abitbol M, Gouni V, Trehiou-Sechi E, Tissier R, Queney G, Pouchelon JL, Thomas A (2010) Prevalence of the MYBPC3-A31P mutation in a large European feline population and association with hypertrophic cardiomyopathy in the Maine Coon breed. J Vet Cardiol 12:155–161

    Article  PubMed  Google Scholar 

  • Matkovich SJ, Van Booven DJ, Hindes A, Kang MY, Druley TE, Vallania FL, Mitra RD, Reilly MP, Cappola TP, Dorn GW 2nd (2010) Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy revealing HSPB7 polymorphisms associated with disease. J Clin Invest 120:280–289

    Article  PubMed  CAS  Google Scholar 

  • McCutcheon LJ, Cory CR, Nowack L (1992) Respiratory chain defect of myocardial mitochondria in idiopathic dilated cardiomyopathy of Doberman pinscher dogs. Can J Phys Pharm 70:1529–1533

    Article  CAS  Google Scholar 

  • Meurs KM, Kittleson M, Spangler E, Ware WA, Womack JE, Towbin JA (2000) Nine polymorphisms within head and hinge region of the feline cardiac B-myosin heavy chain gene. Anim Genet 31:231

    PubMed  CAS  Google Scholar 

  • Meurs KM, Magnon AL, Spier AW, Miller MW, Lehmkuhl LB, Towbin JA (2001) Evaluation of the cardiac actin gene in Doberman pinschers with dilated cardiomyopathy. Am J Vet Res 62:33–36

    Article  PubMed  CAS  Google Scholar 

  • Meurs KM, Fox PR, Norgard MM, Spier AW, Lamb A, Koplitz SL, Baunwart RD (2007) A prospective genetic evaluation of familial dilated cardiomyopathy in the Doberman pinscher. J Vet Intern Med 21:1016–1020

    Article  PubMed  Google Scholar 

  • Meurs KM, Hendrix KP, Norgard MM (2010) Molecular evaluation of five cardiac genes in Doberman pinschers with dilated cardiomyopathy. Am J Vet Res 68:1050–1063

    Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole genome association and population-based linkage analysis. Am J Hum Genet 15:263–265

    Google Scholar 

  • Rozen S, Skaletsky HJ (2003) Primer 3 on the WWW for general users and for biologist programmers. In: Krawetz SA, Misener S (eds) Bioinformatics methods and protocols: methods in molecular biology. Humana Press, New Jersey, pp 365–386

    Google Scholar 

  • Saddik M, Gamble J, Witters LA, Lopaschuk GD (1993) Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem 268:25836–25845

    PubMed  CAS  Google Scholar 

  • Smucker ML, Kaul S, Woodfield JA (1990) Naturally occurring cardiomyopathy in the Doberman pinscher: A possible large animal model of human cardiomyopathy? J Am Coll Card 16:200–206

    Article  CAS  Google Scholar 

  • Stabej P, Imholz S, Veersteeg SA, Zilstra C, Stokhof AA, Domanjko-Petric A, Leegwater PA, van Oost BA (2004) Characterization of the canine desmin gene and evaluation as a candidate gene for dilated cardiomyopathy in the Doberman. Gene 340:241–249

    Article  PubMed  CAS  Google Scholar 

  • Stabej P, Leegwater PA, Imholz S, Veersteeg SA, Zilstra C, Stokhof AA, Domanjko-Petric A, van Oost BA (2005a) The canine sarcoglycan delta gene: BAC clone contig assemby, chromosome assignment and interrogation as a candidate gene for dilated cardiomyopathy in Dobermann dogs. Cytogenetics and Genome Research 111:140–146

    Article  PubMed  CAS  Google Scholar 

  • Stabej P, Leegwater PA, Stokhof AA, Domanjko-Petric A, van Oost BA (2005b) Evaluation of the phospholamban gene in purebred large-breed dogs with dilated cardiomyopathy. Am J Vet Res 66:432–436

    Article  PubMed  CAS  Google Scholar 

  • Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85:1093–1129

    Article  PubMed  CAS  Google Scholar 

  • Wynn RM, Kato M, Chuang JL, Tso SC, Li J, Chuang DT (2010) Pyruvate dehydrogenase kinase-4 structure reveal a metastable open conformation fostering robust core-free basal activity. J Biol Chem 12:25305–25315

    Google Scholar 

  • Yeo G, Burge CB (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377–394

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA

    Kathryn M. Meurs & Bruce W. Keene

  2. Washington State University College of Veterinary Medicine, Pullman, WA, USA

    Kathryn M. Meurs, Sunshine Lahmers & Stephen N. White

  3. USDA-ARS Animal Disease Research Unit, Pullman, WA, USA

    Stephen N. White

  4. University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA

    Mark A. Oyama

  5. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Evan Mauceli & Kerstin Lindblad-Toh

  6. Uppsala University, Uppsala, Sweden

    Kerstin Lindblad-Toh

Authors
  1. Kathryn M. Meurs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sunshine Lahmers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruce W. Keene
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen N. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark A. Oyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Evan Mauceli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kerstin Lindblad-Toh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathryn M. Meurs.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 51 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meurs, K.M., Lahmers, S., Keene, B.W. et al. 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 131, 1319–1325 (2012). https://doi.org/10.1007/s00439-012-1158-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-012-1158-2

Keywords

Search

Navigation