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PubMed1996

Expression of a dystrophin-sarcoglycan complex in serum-deprived BC3H1 cells and involvement of alpha-sarcoglycan in substrate attachment.

Dystrophin and alpha- and gamma-sarcoglycans were newly expressed in BC3H1 cells during differentiation induced by serum withdrawal. These proteins formed a tight complex with other dystophin-associated proteins (DAPs), as detected by immunoprecipitation with anti-dystrophin antibody. Integrins beta 1 and beta 3, vinculin, and focal adhesion kinase were also detected in the same immunoprecipitate. In a cell adhesion assay, differentiated BC3H1 cells attached more efficiently to type I collagen-coated dishes than nondifferentiated cells and loss of alpha-sarcoglycan induced by antisense ODN in differentiated cells resulted in significant inhibition of cell adhesion. Thus dystrophin and DAPs, at least partly, form a complex with the focal adhesion proteins in differentiated BC3H1 cells and alpha-sarcoglycan seems to modulate the function of the focal adhesion complex in these cells.

Animals↗
PubMed1999

Strain- and age-dependent loss of sarcoglycan complex in cardiomyopathic hamster hearts and its re-expression by delta-sarcoglycan gene transfer in vivo.

The delta-sarcoglycan (SG) gene is deleted in hamsters with hereditary cardiomyopathies. Immunological analyses of heart before, but not after, the progression of cardiomyopathy (CM) revealed that the BIO 14.6 strain, a model of hypertrophic CM, heterogeneously preserved alpha- and gamma-SG with loss of beta- and delta-SG. In contrast, the TO-2 strain, a model of dilated CM, did not show either SG. Furthermore, in vivo transfer of the full length delta-SG gene to TO-2 hearts expressed all four SGs. Thus, this age- and strain-dependent features suggest a more feasible setting for TO-2 than BIO 14.6 to verify both CM progression and the efficacy of gene therapy.

Age Factors↗
PubMed2005

Epsilon-sarcoglycan compensates for lack of alpha-sarcoglycan in a mouse model of limb-girdle muscular dystrophy.

Dystrophin and the dystrophin-associated protein (DAP) complex protect the sarcolemma against contraction-induced injury and serve as a mechanical link between the extracellular matrix and the actin cytoskeleton. Some of the functional properties of the DAP complex are mediated by its sarcoglycan (SG) subcomplex, which is composed of alpha-, beta-, gamma- and delta-SGs. Autosomal recessive limb-girdle muscular dystrophy type-2D (LGMD 2D) results from reduction in SG subcomplex levels caused by specific mutations in the muscle-specific alpha-SG gene. epsilon-SG is a widely expressed homolog of the muscle-specific alpha-SG, and expression of epsilon-SG may compensate for the pathologic changes in alpha-SG function. Thus, the goal of the present study was to investigate whether overexpression of epsilon-SG can compensate for dysfunction of alpha-SG. Several transgenic mouse lines that overexpress epsilon-SG in skeletal muscle were established. Overexpression of epsilon-SG in normal mice resulted in substitution of epsilon-SG for alpha-SG in the SG complex of skeletal muscle without any obvious abnormalities. To determine whether an increase in epsilon-SG expression may prevent muscular dystrophy in the context of alpha-SG-deficiency, these epsilon-SG transgenic mice were crossed with alpha-SG deficient mice. alpha-SG-deficient mice overexpressing epsilon-SG exhibited no skeletal muscle cell membrane damage or abnormal contraction. These data suggest that the overexpression of epsilon-SG may represent a therapeutic strategy for treatment of LGMD 2D.

Animals↗
PubMed2002

Defective assembly of sarcoglycan complex in patients with beta-sarcoglycan gene mutations. Study of aneural and innervated cultured myotubes.

Mutations in the sarcoglycan (SG) genes cause autosomal recessive muscular dystrophies. The absence of each SG complex component in muscle impairs the proper assembly of the entire SG complex, resulting in sarcolemmal damage. We investigated the consequences of beta-SG gene mutations in cultured muscle from two beta-SG mutated patients, and analysed each individual SG protein expression by cross-sectional immunocytochemistry and Western blot in aneural and innervated myotubes. Patients' muscle biopsy showed total loss of SG complex; however, a limited amount of beta-SG was detected in aneural and innervated myotubes, where the protein was localized to the plasma membrane. This paradoxical beta-SG expression can be attributable to antibody cross-reaction or to the expression of an unknown SG isoform specific of immature muscle. In our cultured myotubes, the other components of the SG complex were absent, suggesting that beta-SG gene mutations result in a defective assembly of the entire SG complex in early stages of muscle development, and that the role of beta-SG is crucial for the normal structure and/or function of the SG complex in the sarcolemma.

Base Sequence↗
PubMed2005

Sarcoglycan subcomplex in normal human smooth muscle: an immunohistochemical and molecular study.

The sarcoglycans are transmembrane components of the dystrophin-glycoprotein complex, which links the cytoskeleton to the extracellular matrix in adult muscle fibers. Sarcoglycans seem to be functionally and pathologically as important as dystrophin. In the skeletal and cardiac muscle, the sarcoglycan subcomplex is a heterotetrameric unit composed of the transmembrane glycoproteins alpha-, beta-, gamma- and delta-sarcoglycan. A fifth sarcoglycan with significant homology to alpha-sarcoglycan, epsilon-sarcoglycan, has been identified; this sarcoglycan is expressed in both muscle and non-muscle cells. It is hypothesized that epsilon-sarcoglycan might replace alpha-sarcoglycan in smooth muscle, forming a novel sarcoglycan subcomplex consisting of epsilon-, beta-, gamma-, and delta-sarcoglycan. Recently, zeta-sarcoglycan, a novel sarcoglycan highly related to gamma-sarcoglycan and delta-sarcoglycan, has been identified. On this basis, growing evidence suggests that there are two types of sarcoglycan complex; one, in skeletal and cardiac muscle, consisting of alpha-, beta-, gamma- and delta-sarcoglycan; and the other, in smooth muscle, containing beta-, delta-, zeta- and epsilon-sarcoglycan. epsilon-sarcoglycan may be substituted for alpha-sarcoglycan in a subset of striated muscle complexes. Our results, obtained with immunofluorescence semi-quantitative analysis and molecular methods on smooth muscle biopsies of human adult gastroenteric tract, show for the first time that alpha-sarcoglycan fluorescence is also always detectable in smooth muscle, although its staining pattern is lower than epsilon-sarcoglycan. Normal alpha-sarcoglycan staining was detected at times, whereas there was reduced, but clearly detectable staining for epsilon-sarcoglycan. Moreover, gamma-sarcoglycan staining is always detectable in all analyzed biopsies. On the basis of our results, we would be able to hypothesize the existence of a pentameric or, considering zeta-sarcolgycan, a hexameric arrangement of the sarcoglycan subcomplex. The hexameric sarcoglycan subcomplex, in conformity with a larger or lower expression of single sarcoglycans, could characterize skeletal, cardiac or smooth muscle, or distinct parts of gastroenteric tract. It is intriguing to integrate these results with other vascular and urogenital smooth muscle, skeletal and cardiac muscle, while also analyzing zeta-sarcoglycan.

Adult↗
PubMed1999

Sarcoglycan isoforms in skeletal muscle.

The heterotetrameric sarcoglycan complex, composed of alpha-, beta-, gamma-, and delta-sarcoglycans, is an important component of the dystrophin-associated glycoprotein assembly in striated muscle. Mutations in any of the four genes encoding sarcoglycans cause a deficiency in all sarcoglycans in the sarcolemma and produce one of four types of limb-girdle muscular dystrophy. A fifth widely expressed sarcoglycan, epsilon-sarcoglycan, has been recently described. epsilon-Sarcoglycan is homologous to alpha-sarcoglycan, but whether it associates with the other sarcoglycans in muscle is not known. In this study, we use wild type and alpha-sarcoglycan-deficient mice to analyze the localization and association of sarcoglycans in skeletal muscle in vivo. The amounts of beta-, gamma-, and delta-sarcoglycans are reduced in alpha-sarcoglycan mutants, whereas the amount of epsilon-sarcoglycan is unchanged. We show here that epsilon-sarcoglycan is complexed with beta-, gamma-, and delta-sarcoglycans in both wild type and alpha-sarcoglycan mutant mice. We also use C2C12 myocytes to study the temporal expression and organization of sarcoglycan complexes during muscle cell differentiation in vitro. In C2C12 cells, alpha- and epsilon-sarcoglycans form separate complexes with beta-, gamma-, and delta-sarcoglycans. Both types of complexes are expressed at the cell surface and presumed to be functional. These results suggest that epsilon-sarcoglycan serves a function similar to that of alpha-sarcoglycan and that residual beta-, gamma-, and delta-sarcoglycan seen in mutant mice and alpha-sarcoglycan-deficient patients is due to its association with epsilon-sarcoglycan.

Animals↗
PubMedDate not supplied

Sarcoglycans in muscular dystrophy.

Muscular dystrophy is a heterogeneous genetic disease that affects skeletal and cardiac muscle. The genetic defects associated with muscular dystrophy include mutations in dystrophin and its associated glycoproteins, the sarcoglycans. Furthermore, defects in dystrophin have been shown to cause a disruption of the normal expression and localization of the sarcoglycan complex. Thus, abnormalities of sarcoglycan are a common molecular feature in a number of dystrophies. By combining biochemistry, molecular cell biology, and human and mouse genetics, a growing understanding of the sarcoglycan complex is emerging. Sarcoglycan appears to be an important, independent mediator of dystrophic pathology in both skeletal muscle and heart. The absence of sarcoglycan leads to alterations of membrane permeability and apoptosis, two shared features of a number of dystrophies. beta-sarcoglycan and delta-sarcoglycan may form the core of the sarcoglycan subcomplex with alpha- and gamma-sarcoglycan less tightly associated to this core. The relationship of epsilon-sarcoglycan to the dystrophin-glycoprotein complex remains unclear. Animals lacking alpha-, gamma- and delta-sarcoglycan have been described and provide excellent opportunities for further investigation of the function of sarcoglycan. Dystrophin with dystroglycan and laminin may be a mechanical link between the actin cytoskeleton and the extracellular matrix. By positioning itself in close proximity to dystrophin and dystroglycan, sarcoglycan may function to couple mechanical and chemical signals in striated muscle. Sarcoglycan may be an independent signaling or regulatory module whose position in the membrane is determined by dystrophin but whose function is carried out independent of the dystrophin-dystroglycan-laminin axis.

Amino Acid Sequence↗
PubMed1997

Mutations in the sarcoglycan genes in patients with myopathy.

BACKGROUND: Some patients with autosomal recessive limb-girdle muscular dystrophy have mutations in the genes coding for the sarcoglycan proteins (alpha-, beta-, gamma-, and delta-sarcoglycan). To determine the frequency of sarcoglycan-gene mutations and the relation between the clinical features and genotype, we studied several hundred patients with myopathy. METHODS: Antibody against alpha-sarcoglycan was used to stain muscle-biopsy specimens from 556 patients with myopathy and normal dystrophin genes (the gene frequently deleted in X-linked muscular dystrophy). Patients whose biopsy specimens showed a deficiency of alpha-sarcoglycan on immunostaining were studied for mutations of the alpha-, beta-, and gamma-sarcoglycan genes with reverse transcription of muscle RNA, analysis involving single-strand conformation polymorphisms, and sequencing. RESULTS: Levels of alpha-sarcoglycan were found to be decreased on immunostaining of muscle-biopsy specimens from 54 of the 556 patients (10 percent); in 25 of these patients no alpha-sarcoglycan was detected. Screening for sarcoglycan-gene mutations in 50 of the 54 patients revealed mutations in 29 patients (58 percent): 17 (34 percent) had mutations in the alpha-sarcoglycan gene, 8 (16 percent) in the beta-sarcoglycan gene, and 4 (8 percent) in the gamma-sarcoglycan gene. No mutations were found in 21 patients (42 percent). The prevalence of sarcoglycan-gene mutations was highest among patients with severe (Duchenne-like) muscular dystrophy that began in childhood (18 of 83 patients, or 22 percent); the prevalence among patients with proximal (limb-girdle) muscular dystrophy with a later onset was 6 percent (11 of 180 patients). CONCLUSIONS: Defects in the genes coding for the sarcoglycan proteins are limited to patients with Duchenne-like and limb-girdle muscular dystrophy with normal dystrophin and occur in 11 percent of such patients.

Adolescent↗
PubMed2001

delta- and gamma-Sarcoglycan localization in the sarcoplasmic reticulum of skeletal muscle.

Sarcoglycans are transmembrane proteins that are members of the dystrophin complex. Sarcoglycans cluster together to form a complex, which is localized in the cell membrane of skeletal, cardiac, and smooth muscle fibers. However, it is still unclear whether or not sarcoglycans are restricted to the sarcolemma. To address this issue, we examined alpha-, beta-, delta-, and gamma-sarcoglycan expression in femoral skeletal muscle from control and dystrophin-deficient mice and rats using confocal microscopy and immunoelectron microscopy. Confocal microscopy of the tissues in cross-section showed that all sarcoglycans were detected under the sarcolemma in rats and control mice. delta- and gamma-sarcoglycan labeling demonstrated striations in the longitudinal section, suggesting that the proteins were expressed in the sarcoplasmic reticulum (SR) or transverse tubules (T-tubules). Moreover, such striations of both sarcoglycans were recognized in the dystrophin-deficient mouse skeletal muscle. Double labeling with phalloidin or alpha-actinin and delta- or gamma-sarcoglycan showed different labeling patterns, indicating that delta-sarcoglycan localization was distinct from that of gamma-sarcoglycan. Immunoelectron microscopy clarified that delta-sarcoglycan was localized in the terminal cisternae of the SR, while gamma-sarcoglycan was found in the terminal cisternae and longitudinal SR over I-bands but not over A-bands. These data demonstrate that delta- and gamma-sarcoglycans are components of the SR in skeletal muscle, suggesting that both sarcoglycans function independent of the dystrophin complex in the SR.

Actinin↗
PubMed2000

Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex.

Sarcoglycan is a multimeric, integral membrane glycoprotein complex that associates with dystrophin. Mutations in individual sarcoglycan subunits have been identified in inherited forms of muscular dystrophy. To evaluate the contributions of sarcoglycan and dystrophin to muscle membrane stability and muscular dystrophy, we compared muscle lacking specific sarcoglycans or dystrophin. Here we report that mice lacking (delta)-sarcoglycan developed muscular dystrophy and cardiomyopathy similar to mice lacking (gamma)-sarcoglycan. However, unlike muscle lacking (gamma)-sarcoglycan, (delta)-sarcoglycan-deficient muscle was sensitive to eccentric contraction-induced disruption of the plasma membrane. In the absence of (delta)-sarcoglycan, (alpha)-, (beta)- and (gamma)-sarcoglycan were undetectable, while dystrophin was expressed at normal levels. In contrast, without (gamma)-sarcoglycan, reduced levels of (alpha)-, (beta)- and (delta)-sarcoglycan were expressed, glycosylated and formed a complex with each other. Thus, the elimination of (gamma)- and (delta)-sarcoglycan had different molecular consequences for the assembly and function of the dystrophin-glycoprotein complex. Furthermore, these molecular differences were associated with different mechanical consequences for the muscle plasma membrane. Through this in vivo analysis, a model for sarcoglycan assembly is proposed.

Animals↗
PubMed2004

Evaluation of sarcoglycans, vinculin-talin-integrin system and filamin2 in alpha- and gamma-sarcoglycanopathy: an immunohistochemical study.

The sarcoglycan subcomplex (SGC) is a well-known system of interaction between extracellular matrix and sarcolemma-associated cytoskeleton in skeletal and cardiac muscle. The SGC is included in the DGC made up of sarcoplasmic subcomplex and a dystroglycan subcomplex. Recent developments in molecular genetics have demonstrated that the mutation of each single sarcoglycan gene, causes a series of recessive autosomal muscular dystrophies, dystrophin-positive, called sarcoglycanopathies or limb girdle muscular dystrophies. Our recent studies have demonstrated that costameres are a proteic machinery made up of DGC and vinculin-talin-integrin system, also revealing the colocalization of sarcoglycans and integrins in adult human skeletal muscle. These results may support the hypothesis of the existence of a bidirectional signalling between sarcoglycans and integrins in cultured L6 myocytes. The hypothesis of bidirectional signalling between sarcoglycans and integrins could be supported by the identification of a skeletal and cardiac muscle filamin2 as a gamma-sarcoglycan, delta-sarcoglycan and, hypothetically, beta1 integrin interacting protein. Our results, acquired with an immunofluorescence study on adult human skeletal muscle affected by LGMD type 2D and 2C, showed that in LGMD2D: a) alpha-sarcoglycan staining is severely reduced; b) the beta-gamma-delta-sarcoglycan subunit and all tested integrins staining are clearly detectable; c) filamin2 is normal and shows a costameric distribution. In LGMD2C: a) alpha-sarcoglycan staining is preserved; b) the beta-gamma-delta-sarcoglycan subunit staining is severely reduced; c) the alpha7B-integrin is slightly reduced and beta1D-integrin is severely reduced; d) filamin2 is severely reduced. Other tested proteins of the two systems show a normal staining pattern in both sarcoglycanopathies. Our study seems to confirm, for the first time on adult human skeletal muscle of subjects affected by LGMDs, the hypo-theses of: a) the existence, in mouse myotubes in culture, of two distinct subunits in sarcoglycans subcomplex; b) the presence of a bidirectional signalling between sarcoglycans and integrins, previously demonstrated on rat cultured L6 myocytes; c) the interaction of FLN2 with both sarcoglycans and integrins. These results may stimulate the search of yet unidentified common interactors of both fiber-extracellular matrix interaction systems.

Biopsy↗
PubMed2002

Delivery of alpha- and beta-sarcoglycan by recombinant adeno-associated virus: efficient rescue of muscle, but differential toxicity.

The sarcoglycanopathies are a group of four autosomal recessive limb girdle muscular dystrophies (LGMD 2D, 2E, 2C, and 2F), caused by mutations of the alpha-, beta-, gamma-, or delta-sarcoglycan genes, respectively. The delta-sarcoglycan-deficient hamster has been the most utilized model for gene delivery to muscle by recombinant adeno-associated virus (AAV) vectors; however, human patients with delta-sarcoglycan deficiency are exceedingly rare, with only two patients described in the United States. Here, we report construction and use of AAV vectors expressing either alpha- or beta-sarcoglycan, the genes responsible for the most common forms of the human sarcoglycanopathies. Both vectors showed successful short-term genetic, biochemical, and histological rescue of both alpha- and beta-sarcoglycan-deficient mouse muscle. However, comparison of persistence of expression in 51 injected mice showed substantial differences between AAV alpha-sarcoglycan (alpha-SG) and beta-sarcoglycan (beta-SG) vectors. AAV-beta-SG showed long-term expression with no decrease in expression for more than 21 months after injection, whereas AAV-alpha-SG showed a dramatic loss of positive fibers between 28 and 41 days post-injection (p = 0.006). Loss of immunopositive myofibers was correlated with significant inflammatory cell infiltrate, primarily macrophages. To determine whether the loss of alpha-sarcoglycan-positive fibers was due to an immune response or cytotoxic effect of alpha-sarcoglycan overexpression, severe combined immunodeficient (SCID) mouse muscle was assayed for cytotoxicity after injection with AAV-alpha-SG, AAV-beta-SG, or phosphate-buffered saline. The results were consistent with overexpression of alpha-sarcoglycan causing significant cytotoxicity. The cytotoxicity of alpha-sarcoglycan, and not beta- or delta-sarcoglycan overexpression, was consistent with biochemical studies of the hierarchical order of assembly of the sarcoglycan complex. Our data suggest that even closely related proteins might require different levels of expression to avoid toxicity and achieve long-term tissue rescue.

Animals↗
PubMed2000

Molecular and genetic characterization of sarcospan: insights into sarcoglycan-sarcospan interactions.

Autosomal recessive limb girdle muscular dystrophies 2C-2F represent a family of diseases caused by primary mutations in the sarcoglycan genes. We show that sarcospan, a novel tetraspan-like protein, is also lost in patients with either a complete or partial loss of the sarcoglycans. In particular, sarcospan was absent in a gamma-sarcoglycanopathy patient with normal levels of alpha-, beta- and delta-sarcoglycan. Thus, it is likely that assembly of the complete, tetrameric sarcoglycan complex is a prerequisite for membrane targeting and localization of sarcospan. Based on our findings that sarcospan is integrally associated with the sarcoglycans, we screened >50 autosomal recessive muscular dystrophy cases for mutations in sarcospan. Although we identified three intragenic polymorphisms, we did not find any cases of muscular dystrophy associated with primary mutations in the sarcospan gene. Finally, we have identified an important case of limb girdle muscular dystrophy and cardiomyopathy with normal expression of sarcospan. This patient has a primary mutation in the gamma-sarcoglycan gene, which causes premature truncation of gamma-sarcoglycan without affecting assembly of the mutant gamma-sarcoglycan into a complex with alpha-, beta- and delta-sarcoglycan and sarcospan. This is the first demonstration that membrane expression of a mutant sarcoglycan-sarcospan complex is insufficient in preventing muscular dystrophy and cardiomyopathy and that the C-terminus of gamma-sarcoglycan is critical for the functioning of the entire sarcoglycan-sarcospan complex. These findings are important as they contribute to a greater understanding of the structural determinants required for proper sarcoglycan-sarcospan expression and function.

Adult↗
PubMed1997

Genetic epidemiology of muscular dystrophies resulting from sarcoglycan gene mutations.

BACKGROUND: The autosomal recessive limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous muscle diseases characterised by progressive proximal limb muscle weakness. Six different loci have been mapped and pathogenetic mutations in the genes encoding the sarcoglycan complex components (alpha-, beta-, gamma-, and delta-sarcoglycan) have been documented. LGMD patients affected with primary "sarcoglycanopathies" are classified as LGMD2D, 2E, 2C, and 2F, respectively. METHODS: A geographical area in north east Italy (2,319,147 inhabitants) was selected for a genetic epidemiological study on primary sarcoglycanopathies. Within the period 1982 to 1996, all patients living in this region and diagnosed with muscular dystrophy were seen at our centre. Immunohistochemical and immunoblot screening for alpha-sarcoglycan protein deficiency was performed on all muscle biopsies from patients with a progressive muscular dystrophy of unknown aetiology and normal dystrophin. Sarcoglycan mutation analyses were conducted on all patient muscle biopsies shown to have complete or partial absence of alpha-sarcoglycan immunostaining or a decreased quantity of alpha-sarcoglycan protein on immunoblotting. RESULTS: Two hundred and four patient muscle biopsies were screened for alpha-sarcoglycan protein deficiency and 18 biopsies showed a deficiency. Pathogenetic mutations involving one gene for sarcoglycan complex components were identified in 13 patients: alpha-sarcoglycan in seven, beta-sarcoglycan in two, gamma-sarcoglycan in four, and none in the delta-sarcoglycan gene. The overall prevalence of primary sarcoglycanopathies, as of 31 December 1996, was estimated to be 5.6 x 10(-6) inhabitants. CONCLUSION: The prevalence rate estimated in this study is the first to be obtained after biochemical and molecular genetic screening for sarcoglycan defects.

Adolescent↗
PubMed2006

Delta-sarcoglycan is necessary for early heart and muscle development in zebrafish.

Delta-sarcoglycan, one member of the sarcoglycan complex, is a very conservative muscle-specific protein exclusively expressed in the skeletal and cardiac muscles of vertebrates. Mutations in sarcoglycans are known to be involved in limb-girdle muscular dystrophy (LGMD) and dilated cardiomyopathy (DCM) in humans. To address the role of delta-sarcoglycan gene in zebrafish development, we have studied expression pattern of delta-sarcoglycan in zebrafish embryos and examined the role of delta-sarcoglycan in zebrafish embryonic development by morpholino. Strong expression of delta-sarcoglycan was observed in various muscles including those of the segment, heart, eye, jaw, pectoral fin, branchial arches, and swim bladder in zebrafish embryo. Delta-sarcoglycan was also expressed in midbrain and retina. Knockdown of delta-sarcoglycan resulted in severe abnormality in both the cardiac and skeletal muscles. Some severe ones displayed serious morphological abnormality such as hypoplastic head, linear heart, very weak heartbeats, and runtish trunk, all dead within 5 dpf. Whole-mount in situ hybridization analysis showed that adaxial cells and muscle pioneers were affected in delta-sarcoglycan knockdown embryos. In addition, absence of delta-sarcoglycan protein severely delayed the cardiac development and influenced the differentiation of cardiac muscle, and the cardiac left-right asymmetry was dramatically changed in morpholino-treated embryos. These data together suggest that delta-sarcoglycan plays an important role in early heart and muscle development.

Animals↗
PubMed1998

Gamma-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin.

gamma-Sarcoglycan is a transmembrane, dystrophin-associated protein expressed in skeletal and cardiac muscle. The murine gamma-sarcoglycan gene was disrupted using homologous recombination. Mice lacking gamma-sarcoglycan showed pronounced dystrophic muscle changes in early life. By 20 wk of age, these mice developed cardiomyopathy and died prematurely. The loss of gamma-sarcoglycan produced secondary reduction of beta- and delta-sarcoglycan with partial retention of alpha- and epsilon-sarcoglycan, suggesting that beta-, gamma-, and delta-sarcoglycan function as a unit. Importantly, mice lacking gamma-sarco- glycan showed normal dystrophin content and local- ization, demonstrating that myofiber degeneration occurred independently of dystrophin alteration. Furthermore, beta-dystroglycan and laminin were left intact, implying that the dystrophin-dystroglycan-laminin mechanical link was unaffected by sarcoglycan deficiency. Apoptotic myonuclei were abundant in skeletal muscle lacking gamma-sarcoglycan, suggesting that programmed cell death contributes to myofiber degeneration. Vital staining with Evans blue dye revealed that muscle lacking gamma-sarcoglycan developed membrane disruptions like those seen in dystrophin-deficient muscle. Our data demonstrate that sarcoglycan loss was sufficient, and that dystrophin loss was not necessary to cause membrane defects and apoptosis. As a common molecular feature in a variety of muscular dystrophies, sarcoglycan loss is a likely mediator of pathology.

Animals↗
PubMed2005

Epsilon-sarcoglycan immunoreactivity and mRNA expression in mouse brain.

Myoclonus dystonia (M-D) is a hereditary movement disorder caused by a maternally imprinted gene that is often associated with psychiatric symptoms. Most cases of M-D are believed to result from mutations of the epsilon-sarcoglycan protein. The neuroanatomical distribution of epsilon-sarcoglycan-like immunoreactivity in mouse was investigated by using an antiserum against the epsilon-sarcoglycan protein. The expression of epsilon-sarcoglycan mRNA was studied by a sensitive fluorescence in situ hybridization (FISH) method. Immunohistochemistry and FISH revealed a wide distribution of epsilon-sarcoglycan protein and mRNA throughout the mouse brain. High expression levels of epsilon-sarcoglycan mRNA and immunoreactivity were found in the mitral cell layer of the olfactory bulb, the Purkinje cell layer in cerebellum, and the monoaminergic neurons in the mouse midbrain. Immunohistochemistry revealed a similar distribution of epsilon-sarcoglycan protein. Double-labeling FISH showed colocalization of tyrosine hydroxylase and epsilon-sarcoglycan mRNAs within all the midbrain dopaminergic (DAergic) cell groups. By combining FISH with fluorescence immunohistochemistry, coexpression of epsilon-sarcoglycan mRNA and tryptophan hydroxylase immunoreactivity was found in the serotonergic (5-HTergic) neurons within the dorsal raphe nucleus. The distribution of epsilon-sarcoglycan in the mouse brain suggests that the symptom complex of M-D may be related to the effects of decreased epsilon-sarcoglycan activity on the development or function of monoaminergic neurons.

Animals↗
PubMed1999

Ultrastructural localization of alpha-, beta- and gamma-sarcoglycan and their mutual relation, and their relation to dystrophin, beta-dystroglycan and beta-spectrin in normal skeletal myofiber.

Ultrastructural localization of alpha-, beta- and gamma-sarcoglycan and their mutual relation, and their relation to dystrophin, beta-dystroglycan and beta-spectrin were investigated in normal skeletal myofibers. Single-immunogold labeling electron microscopy showed that the signals of rabbit and sheep polyclonal antibodies against the synthetic peptide of the cytoplasmic domain of alpha-, beta or gamma-sarcoglycan were present along the inside surface of muscle plasma membrane and at the sarcoplasmic side of plasma membrane invaginations and vesicular structures in subsarcolemmal areas. These localizations were similar to that of dystrophin, beta-dystroglycan and beta-spectrin. Double-immunogold labeling disclosed the close association of alpha-, beta- and gamma-sarcoglycan each other and alpha-, beta-, gamma-sarcoglycan with dystrophin or beta-dystroglycan, and this was confirmed by statistical analysis. Monoclonal antibody against the extracellular domain of alpha-sarcoglycan was used with above-mentioned polyclonal anti-beta- and -gamma-sarcoglycan antibodies for triple-immunogold labeling, in which signals of alpha-sarcoglycan localized at the outer surface of muscle plasmalemma and those of beta- and gamma-sarcoglycans were present at the inside surface of plasma membrane. The triple immunolabeling showed an occasional closely associated presence of the three signals for alpha-, beta-and gamma-sarcoglycans, and a more frequent association for two signals out of alpha-, beta- and gamma-sarcoglycans. This study demonstrated that alpha-, beta- and gamma-sarcoglycan are closely located to one another and to dystrophin and beta-dystroglycan at the muscle plasma membrane.

Animals↗