Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, δ-sarcoglycan, in hamster: An animal model of disrupted dystrophin-associated glycoprotein complex

Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, δ-sarcoglycan, in hamster: An animal model of disrupted dystrophin-associated glycoprotein complex

^*The Second Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113, ^†Cellular Physiology Laboratory, The Institute of Physical and Chemical Research (RIKEN), 2–1 Hirosawa, Wako-shi, Saitama 351–01, and ^§Division of Chemical Pharmacology and Phytochemistry, National Institute of Health Sciences, 1–18-1 Kami-Yohga, Setagaya-ku, Tokyo 158, Japan; ^¶Department of Pathology, Faculty of Medicine, University of Montreal, CP6128, Succursale A, Montreal, Quebec H3C 3J7, Canada; and ^‖Department of Pharmacology, Faculty of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606, Japan

Communicated by Setsuro Ebashi, National Institute for Physiological Sciences, Okazaki, Japan (received for review April 9, 1997)

Abstract

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 δ-sarcoglycan (δ-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 δ-SG gene, and its 5′ upstream region of more than 27.4 kb, including the authentic first exon of δ-SG gene, was deleted. This deletion included the major transcription initiation site, resulting in a deficiency of δ-SG transcripts with the consequent loss of δ-SG protein in all the CM hamsters, despite the fact that the protein coding region of δ-SG starting from the second exon was conserved in all the CM hamsters. We elucidated the molecular interaction of dystrophin-associated glycoproteins including δ-SG, by using an in vitro pull-down study and ligand overlay assay, which indicates the functional role of δ-SG in stabilizing sarcolemma. The present study not only identifies CM hamster as a valuable animal model for studying the function of δ-SG in vivo but also provides a genetic target for diagnosis and treatment of human CM.

Footnotes

↵ ‡ To whom reprint requests should be addressed at: Cellular Physiology Laboratory, The Institute of Physical and Chemical Research (RIKEN), 2–1 Hirosawa, Wako-shi, Saitama 351–01, Japan. e-mail: aiji{at}postman.riken.go.jp.
Data deposition: The sequences reported in this paper have been deposited in the DDBJ, EMBL, and GenBank databases [accession nos. D83651 (hamster α-SG cDNA), D83652 (hamster β-SG cDNA), D83653 (hamster γ-SG cDNA), AB001508 (hamster δ-SG cDNA), AB007020 (alternative first exon of hamster δ-SG), AB001509 (hamster δ-SG genomic DNA around the first exon), AB007021 (hamster δ-SG genomic DNA around the second exon), AB007022 (hamster δ-SG genomic DNA within the first intron) and AB007023 (CM hamster genomic DNA around the deletion breakpoint)].
ABBREVIATIONS:

CM,

cardiomyopathy;

HCM,

hypertrophic CM;

DCM,

dilated CM;

DAGC,

dystrophin-associated glycoprotein complex;

SG,

sarcoglycan;

DG,

dystroglycan;

EC,

extracellular;

LV,

left ventricle;

CM hamster,

cardiomyopathic hamster;

RT-PCR,

reverse transcription-coupled PCR;

RACE,

rapid amplification of cDNA ends