Both hypertrophic and dilated cardiomyopathies are caused by mutation of 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 and is traditionally categorized into hypertrophic and dilated CMs (HCM and DCM) according to its gross appearance. Cardiomyopathic hamster (CM hamster), a representative model of human hereditary CM, has HCM and DCM inbred sublines, both of which descend from the same ancestor. Herein 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 is yet to be characterized. A breakpoint causing genomic deletion was found to be located at 6.1 kb 5' upstream of the second exon of delta-SG 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 included the major transcription initiation site, resulting in a deficiency of delta-SG transcripts with the consequent loss of delta-SG protein in all the CM hamsters, despite the fact that the protein coding region of delta-SG starting from the second exon was conserved in all the CM hamsters. We elucidated the molecular interaction of dystrophin-associated glycoproteins including delta-SG, by using an in vitro pull-down study and ligand overlay assay, which indicates the functional role of delta-SG in stabilizing sarcolemma. The present study not only identifies CM hamster as a valuable animal model for studying the function of delta-SG in vivo but also provides a genetic target for diagnosis and treatment of human CM.
Sakamoto
A
A
The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. aiji@postman.riken.go.jp
Ono
K
K
Abe
M
M
Jasmin
G
G
Eki
T
T
Murakami
Y
Y
Masaki
T
T
Toyo-oka
T
T
Hanaoka
F
F
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism; D005091:Exons; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008647:Mesocricetus; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D049031:Sarcoglycans; D017384:Sequence Deletion; D014018:Tissue Distribution
D003598:Cytoskeletal Proteins; D017931:DNA Primers; D016189:Dystrophin; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D049031:Sarcoglycans