Mutations in the human ∂-sarcoglycan gene in familial and sporadic dilated cardiomyopathy

Department of Pediatrics, Toyama Medical and Pharmaceutical University, Toyama, Japan.
Journal of Clinical Investigation (Impact Factor: 13.22). 10/2000; 106(5):655-62. DOI: 10.1172/JCI9224
Source: PubMed


Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), whereas three other genes (actin, lamin A/C, and desmin) cause autosomal dominant DCM; seven other loci for autosomal dominant DCM have been mapped but the genes have not been identified. Hypothesizing that DCM is a disease of the cytoskeleton and sarcolemma, we have focused on candidate genes whose products are found in these structures. Here we report the screening of the human delta-sarcoglycan gene, a member of the dystrophin-associated protein complex, by single-stranded DNA conformation polymorphism analysis and by DNA sequencing in patients with DCM. Mutations affecting the secondary structure were identified in one family and two sporadic cases, whereas immunofluorescence analysis of myocardium from one of these patients demonstrated significant reduction in delta-sarcoglycan staining. No skeletal muscle disease occurred in any of these patients. These data suggest that delta-sarcoglycan is a disease-causing gene responsible for familial and idiopathic DCM and lend support to our "final common pathway" hypothesis that DCM is a cytoskeletalopathy.

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Available from: Jeffrey A Towbin, Mar 12, 2014
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    • "d-Sarcoglycan, another component of the dystrophin-glycoprotein complex, is mutated and reduced in patients that present with DCM. Thus, loss and mutations of d-sarcoglycan may be specifically associated with cardiac rather skeletal myopathies (Tsubata et al., 2000). In support of this, mice deficient for d-but not a-sarcoglycan developed cardiomyopathy, necrosis, and fibrosis with increased mortality around 6 months of age (Coral-Vazquez et al., 1999). "
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    • "Since Geisterfer-Lowrance, et al.[8] reported the first HCM-causing mutation of β-myosin heavy chain (β-MyHC) gene in 1990, a large number of mutations in sarcomeric protein genes that encode β-MyHC, cardiac troponin T (cTnT), cardiac troponin I (cTnI), cardiac troponin C (cTnC), α-tropomyosin (α-Tm), cardiac myosin binding protein C (MyBP-C), ventricular myosin light chains 1 and 2 (LC1, LC2), actin and titin/connection, etc.,[2],[8]–[16] as well as cytoskeletal and nuclear membrane protein genes that encode dystrophin, desmin, tafazzin, δ-sarcoglycan, lamin A/C, etc.,[17]–[20] have been identified as a cause of HCM, DCM and RCM. In contrast, no sarcomeric protein genes have been shown to be responsible for ARVC. "
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    • "Patients with mutations in the delta-sarcoglycan gene may present with limb girdle muscular dystrophy 2F [12], [13] together with cardiac involvement [14], or isolated cardiomyopathy [15], [16]. The BIO14.6 hamster [17] is an appropriate model for the human disease. "
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