BOTH HYPERTROPHIC AND DILATED CARDIOMYOPATHIES ARE CAUSED BY MUTATIONOF THE SAME GENE, DELTA-SARCOGLYCAN, IN HAMSTER - AN ANIMAL-MODEL OF DISRUPTED DYSTROPHIN-ASSOCIATED GLYCOPROTEIN COMPLEX

Cardiomyopathy (CM) is a primary degenerative disease of myocardium an d is traditionally categorized into hypertrophic and dilated CMs (HCM and DCM) according to its gross appearance. Cardiomyopathic hamster (C M hamster), a representative model of human hereditary CM, has HCM and DCM inbred sublines, both of which descend from the same ancestor. He rein we show that both HCM and DCM hamsters share a common defect in a gene for delta-sarcoglycan (delta-SG), the functional role of which i s yet to be characterized. A breakpoint causing genomic deletion was f ound to be located at 6.1 kb 5' upstream of the second exon of delta-S G gene, and its 5' upstream region of more than 27.4 kb, including the authentic first exon of delta-SG gene, was deleted. This deletion inc luded the major transcription initiation site, resulting in a deficien cy of delta-SG transcripts with the consequent loss of delta-SG protei n in all the CM hamsters, despite the fact that the protein coding reg ion of delta-SG starting from the second exon was conserved in all the CM hamsters. We elucidated the molecular interaction of dystrophin-as sociated glycoproteins including delta-SG, by using an in vivo pull-do wn study and ligand overlay assay, which indicates the functional role of delta-SG in stabilizing sarcolemma. The present study not only ide ntifies CM hamster as a valuable animal model for studying the functio n of delta-SG in vivo but also provides a genetic target for diagnosis and treatment of human CM.