Molecular genetics of dilated cardiomyopathy in the Dobermann dog

Abstract

Canine dilated cardiomyopathy (DCM) is a disease of the myocardium associated with dilatation and impaired contraction of the ventricles. It primarily affects large and giant breed dogs with Dobermanns being one of the most frequently affected. The high prevalence of DCM in specific breeds suggests a genetic background, but causal mutations have not yet been identified. The main objective of the study described in this thesis was to identify the gene(s) involved in DCM in the Dobermann. For that purpose, the genes of interest were evaluated. Due to close similarities in human and canine DCM, mutated genes identified to cause DCM in the human are good candidate genes for DCM in dogs. At the outset of the DCM research project in 2001, most of the DCM candidate genes had not yet been mapped and the dog genome resources were limited. Therefore, bacterial artificial chromosome (BAC) clones carrying the genes of interest were isolated from the canine BAC library. Microsatellite markers isolated from the BAC clones were typed in the Dobermanns and evaluated for association with the DCM phenotype. While the genes encoding desmin, phospholamban, ?-tropomyosin and ?-sarcoglycan were excluded as DCM causing genes, the genotyping results of the titin markers point to a crucial role of titin in DCM susceptibility. The genetic markers and sequencing oligonucleotide primers reported in this thesis are tools that will enable fast evaluation of the DCM candidate genes in breeds other than the Dobermann. Further research into the role of the titin in canine DCM will also lead to better understanding of cardiomyocyte physiology and pathophysiology of DCM.