Identification of a new missense mutation in the mtDNA of hereditary hypertrophic, but not dilated cardiomyopathic hamsters

The cardiomyopathic hamster is characterized by a naturally occurring deletion in the delta-sarcoglycan gene generating either the hypertrophic or the dilatative phenotype of cardiomyopathy. This evidence suggests that other genetic or environmental factors might concur to the pathogenesis of cardiomyopathy. The aim of the present study was to investigate on the possibility that other genes are involved in the pathogenesis of hamster cardiomyopathy. For this purpose, a series of genes of cardiomyopathic and healthy hamsters were compared by the differential display technique. The hamster cytochrome c oxidase mitochondrial subunit III (COIII) gene has been sequenced and identified as the gene upregulated in brain and skeletal muscle. The gene sequencing and restriction analysis demonstrated that a missense mutation is present in the COIII gene of hamsters exhibiting hypertrophic cardiomyopathy while no mutations were present in dilatative cardiomyopathic hamsters. The mutation was heteroplasmic and the heteroplasmy level was increased with age in skeletal muscle and heart. The ultrastructural analysis of cardiac tissue showed severe damage in the mitochondrial structure of hypertrophic but not dilatative hamster hearts. These results suggest that the pathogenesis of the cardiac damage in hypertrophic cardiomyopathic hamster may be sustained by multiple mutations exerting a cumulative effect on both structure and function of cardiac muscle.