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

Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
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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    • "In cases of LGMD-2F-causing mutations reported so far, five (p.E93X, p.A131P, p.R165X, p.E262K, and c.656C) are located in the extracellular domain and only one (p.W30X) is located in the intracellular domain of the δ-SG protein30313233. In cases of DCM-causing mutations in the δ-SG gene, all three (p.S151A, c.K238, and p.R71T) are located at the extracellular domain [18, 21, 22]. p.S151A disrupted the nuclear localization of lamin A/C and emerin in cardiomyocytes due to nuclear sequestration of mutant δ-SG [44] . "
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    ABSTRACT: The role of genetic abnormality of δ-sarcoglycan (δ-SG) gene in dilated (DCM) and hypertrophied (HCM) cardiomyopathy patients is still unfolding. In this study we first defined the promoter region and then searched for polymorphisms/mutations among the promoter, 5'-untranslated region, and the encoding exons in δ-SG gene in 104 Chinese patients with DCM, 145 with HCM, and 790 normal controls. Two novel polymorphisms were found, an 11 base-pair (bp) deletion (c.-100~-110; -) in the promoter region and a missense polymorphism of A848G resulting in p.Q283R in the highly conserved C-terminus. The prevalence of homozygous genotype -/- of c.-100~-110 was slightly higher in DCM (14.42%) and HCM patients (14.48%), as compared with normal controls (11.01%). The prevalence of genotype of 848A/G was significantly higher in DCM (6.73%; OR = 9.43; p = 0.0002), but not in HCM patients (1.38%; OR = 1.37; p = 0.62), as compared with controls (0.76%). Haplotype -_G consisting c.-100~-110 and A848G was associated with increased risk of DCM (OR = 17.27; 95%CI = 3.19-93.56; p = 0.001) but not associated with HCM (OR = 1.90; 95%CI = 0.38-9.55; p = 0.44). Co-occurrence of the genotypes -/- of c.-100~-110 and 848A/G was found in 5 patients with DCM (4.81%; OR = 39.85; p = 0.0001), none of HCM patients, and only 1 of the controls (0.13%). Both polymorphisms were also found in the Japanese population, but not in the Africans and Caucasians. C.-100~-110 resulted in a decrease of δ-SG promoter activity to 64±3% of the control level (p<0.01). Both co-immunoprecipitation and in vitro protein pull-down assays demonstrated that δ-SG-283R interacts normally to β- and γ-SG, but significantly decreased localization of β/δ/γ-SG on the plasma membrane. In conclusion, haplotype -_G composed of c.-100~-110 and A848G confers higher susceptibility to DCM in the Mongoloid population.
    Full-text · Article · Dec 2015 · PLoS ONE
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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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    ABSTRACT: Heart failure is one of the paramount global causes of morbidity and mortality. Despite this pandemic need, the available clinical counter-measures have not altered substantially in recent decades, most notably in the context of pharmacological interventions. Cell death plays a causal role in heart failure, and its inhibition poses a promising approach that has not been thoroughly explored. In previous approaches to target discovery, clinical failures have reflected a deficiency in mechanistic understanding, and in some instances, failure to systematically translate laboratory findings toward the clinic. Here, we review diverse mouse models of heart failure, with an emphasis on those that identify potential targets for pharmacological inhibition of cell death, and on how their translation into effective therapies might be improved in the future.
    Full-text · Article · Jun 2014 · Current Topics in Developmental Biology
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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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    ABSTRACT: Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), or restrictive cardiomyopathy (RCM). Most functional analyses of the effects of mutations on cardiac muscle contraction have revealed significant changes in the Ca(2+)-regulatory mechanism, in which cardiac troponin (cTn) plays important structural and functional roles as a key regulatory protein. Over a hundred mutations have been identified in all three subunits of cTn, i.e., cardiac troponins T, I, and C. Recent studies on cTn mutations have provided plenty of evidence that HCM- and RCM-linked mutations increase cardiac myofilament Ca(2+) sensitivity, while DCM-linked mutations decrease it. This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca(2+) sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy.
    Full-text · Article · Mar 2013 · Journal of Geriatric Cardiology
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