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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.

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 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.

SUBMITTER: Sakamoto A

PROVIDER: S-EPMC28400 | biostudies-literature | 1997 Dec

REPOSITORIES: biostudies-literature

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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.

Sakamoto A A 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

Proceedings of the National Academy of Sciences of the United States of America 19971201 25

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 b ...[more]

PMID: 9391120

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Project description:Practical relevanceHypertrophic cardiomyopathy (HCM) is the most common form of feline cardiomyopathy observed clinically and may affect up to approximately 15% of the domestic cat population, primarily as a subclinical disease. Fortunately, severe HCM, leading to heart failure or arterial thromboembolism (ATE), only occurs in a small proportion of these cats.Patient groupDomestic cats of any age from 3 months upward, of either sex and of any breed, can be affected. A higher prevalence in male and domestic shorthair cats has been reported.DiagnosticsSubclinical feline HCM may or may not produce a heart murmur or gallop sound. Substantial left atrial enlargement can often be identified radiographically in cats with severe HCM. Biomarkers should not be relied on solely to diagnose the disease. While severe feline HCM can usually be diagnosed via echocardiography alone, feline HCM with mild to moderate left ventricular (LV) wall thickening is a diagnosis of exclusion, which means there is no definitive test for HCM in these cats and so other disorders that can cause mild to moderate LV wall thickening (eg, hyperthyroidism, systemic hypertension, acromegaly, dehydration) need to be ruled out.Key findingsWhile a genetic cause of HCM has been identified in two breeds and is suspected in another, for most cats the cause is unknown. Systolic anterior motion of the mitral valve (SAM) is the most common cause of dynamic left ventricular outflow tract obstruction (DLVOTO) and, in turn, the most common cause of a heart murmur with feline HCM. While severe DLVOTO is probably clinically significant and so should be treated, lesser degrees probably are not. Furthermore, since SAM can likely be induced in most cats with HCM, the distinction between HCM without obstruction and HCM with obstruction (HOCM) is of limited importance in cats. Diastolic dysfunction, and its consequences of abnormally increased atrial pressure leading to signs of heart failure, and sluggish atrial blood flow leading to ATE, is the primary abnormality that causes clinical signs and death in affected cats. Treatment (eg, loop diuretics) is aimed at controlling heart failure. Preventive treatment (eg, antithrombotic drugs) is aimed at reducing the risk of complications (eg, ATE).ConclusionsMost cats with HCM show no overt clinical signs and live a normal or near-normal life despite this disease. However, a substantial minority of cats develop overt clinical signs referable to heart failure or ATE that require treatment. For most cats with clinical signs caused by HCM, the long-term prognosis is poor to grave despite therapy.Areas of uncertaintyGenetic mutations (variants) that cause HCM have been identified in a few breeds, but, despite valiant efforts, the cause of HCM in the vast majority of cats remains unknown. No treatment currently exists that reverses or even slows the cardiomyopathic process in HCM, again despite valiant efforts. The search goes on.

Dataset Information

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.

Publications

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.

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