Article

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

Department of Pediatrics, Toyama Medical and Pharmaceutical University, Toyama, Japan.
Journal of Clinical Investigation (Impact Factor: 13.77). 10/2000; 106(5):655-62. DOI: 10.1172/JCI9224
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Jeffrey A Towbin, Mar 12, 2014
0 Followers
 · 
77 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Current Topics in Developmental Biology 01/2014; 109:171-247. DOI:10.1016/B978-0-12-397920-9.00002-0 · 4.21 Impact Factor
  • Source
    • "Several forms of muscular dystrophy are caused by primary mutations in the genes encoding components of the DAPC [Monaco, 1989; Tsubata et al., 2000]. Primary mutations in the dystrophin gene cause DMD [Darras et al., 1988], which is characterized by the loss of dystrophin protein and concomitant loss of the entire DAPC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dystrophin and dystrophin-associated proteins (DAPs) form a complex around the sarcolemma, which gives stability to the sarcolemma and leads signal transduction. Recently, the nuclear presence of dystrophin Dp71 and DAPs has been revealed in different non-muscle cell types, opening the possibility that these proteins could also be present in the nucleus of muscle cells. In this study, we analyzed by Immunofluorescence assays and Immunoblotting analysis of cell fractions the subcellular localization of Dp71 and DAPs in the C(2)C(12) muscle cell line. We demonstrated the presence of Dp71, alpha-sarcoglycan, alpha-dystrobrevin, beta-dystroglycan and alpha-syntrophin not only in plasma membrane but also in the nucleus of muscle cells. In addition, we found by Immunoprecipitation assays that these proteins form a nuclear complex. Interestingly, myogenesis modulates the presence and/or relative abundance of DAPs in the plasma membrane and nucleus as well as the composition of the nuclear complex. Finally, we demonstrated the presence of Dp71, alpha-sarcoglycan, beta-dystroglycan, alpha-dystrobrevin and alpha-syntrophin in the C(2)C(12) nuclear envelope fraction. Interestingly, alpha-sarcoglycan and beta-dystroglycan proteins showed enrichment in the nuclear envelope, compared with the nuclear fraction, suggesting that they could function as inner nuclear membrane proteins underlying the secondary association of Dp71 and the remaining DAPs to the nuclear envelope. Nuclear envelope localization of Dp71 and DAPs might be involved in the nuclear envelope-associated functions, such as nuclear structure and modulation of nuclear processes.
    Journal of Cellular Biochemistry 10/2008; 105(3):735-45. DOI:10.1002/jcb.21870 · 3.37 Impact Factor
  • Source
    • "LGMD2C-F Alpha, beta, gamma, delta sarcoglycan Part of dystrophin glycoprotein complex in plasma membrane Delta sarcoglycan: dilated cardiomyopathy [21] [22] LGMD2G Telethonin Sarcomeric localisation [23] LGMD2H TRIM32 Ubiquitin ligase Sarcotubular myopathy, "
    [Show abstract] [Hide abstract]
    ABSTRACT: The limb-girdle muscular dystrophies are a group of disorders where our understanding of their underlying molecular basis has made huge strides over the past years, revealing great heterogeneity at the clinical and molecular level. The availability of direct protein and/ or gene based approaches to diagnosis means that these disorders can now be precisely defined, and such definition of a precise diagnosis is increasingly allowing directed management for these diseases by the ability to predict specific complications such as those of the cardiac or respiratory systems. An algorithm combining clinical, biochemical and molecular testing is described which will aid precision of diagnosis and direct specific testing towards the cases most likely to benefit. This brings advantages for the patients of today in recognising the specific risks of their disorders, and in the future will be the starting point for specific gene and protein based therapies.
    Biochimica et Biophysica Acta 03/2007; 1772(2):238-42. DOI:10.1016/j.bbadis.2006.09.009 · 4.66 Impact Factor
Show more