73 Molecular and Cellular Biochemistry 252: 73–81, 2003. © 2003 Kluwer Academic Publishers. Printed in the Netherlands. Identification of a new missense mutation in the mtDNA of hereditary hypertrophic, but not dilated cardiomyopathic hamsters Marilena Minieri, 1 Mara Zingarelli, 1 Huda Shubeita, 2 Alba Vecchini, 3 Luciano Binaglia, 3 Felicia Carotenuto, 1 Cristina Fantini, 1 Roberta Fiaccavento, 1 Laura Masuelli, 4 Anna Coletti, 4 Lucilla Simonelli, 4 Andrea Modesti 5 and Paolo Di Nardo 1 1 Laboratorio di Cardiologia Molecolare e Cellulare, Dipartimento di Medicina Interna, Università di Roma ‘Tor Vergata’, Roma, Italy; 2 Department of Biology, San Diego State University, San Diego, CA, USA; 3 Istituto di Biochimica e Chimica Medica, Università di Perugia, Perugia; 4 Dipartimento di Medicina Sperimentale e Patologia, Università di Roma ‘La Sapienza’, Roma; 5 Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Università di Roma ‘Tor Vergata’, Roma, Italy Received 5 September 2002; accepted 9 January 2003 Abstract The cardiomyopathic hamster is characterized by a naturally occurring deletion in the δ-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 possi- bility 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 oxi- dase 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 ultrastruc- tural 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. (Mol Cell Biochem 252: 73–81, 2003) Key words: hamster cardiomyopathy, mitochondrial DNA, missense mutation, cytochrome c oxidase Introduction Hereditary hypertrophic cardiomyopathy (HHC) is a genetic myocardial disorder characterized by ventricular hypertrophy not related to hypertensive, valvular, congenital or ischemic disease. In human beings, several mutations of genes coding for sarcomeric proteins have been correlated with HHC [1]. Nevertheless, the possibility that other genes and/or environ- mental factors might modulate the expression of mutated genes cannot be discarded, as suggested by the phenotypic variability Address for offprints: P. Di Nardo, Laboratorio di Cardiologia Molecolare e Cellulare, Dipartimento di Medicina Interna, Università di Roma ‘Tor Vergata’, I-00133 Roma, Italy (E-mail: dinardo@med.uniroma2.it)