Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Sarcoglycans”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1998

Different manners of sarcoglycan expression in genetically proven alpha-sarcoglycan deficiency and gamma-sarcoglycan deficiency.

We investigated the expression of alpha-sarcoglycan, beta-sarcoglycan, gamma-sarcoglycan, and delta-sarcoglycan immunohistochemically in three patients with mutations of the alpha-sarcoglycan gene and a patient with a mutation of the gamma-sarcoglycan gene. Although each of the four sarcoglycans were decreased on the muscle membranes of all the patients, different expression patterns for each were seen among the patients. In patients with mutations of the alpha-sarcoglycan gene, beta-, gamma- and delta-sarcoglycans were relatively preserved as compared to greatly reduced alpha-sarcoglycan. However, the patient with a mutation of the gamma-sarcoglycan gene showed marked reduction of gamma-sarcoglycan as compared to partially preserved alpha- and beta-sarcoglycans, and well-preserved delta-sarcoglycan. These results suggest that each sarcoglycan component in sarcoglycanopathy does not decrease in the same manner, and that mutations of the sarcoglycan gene can be predicted, at least in part, by means of sensitive immunohistochemistry for each sarcoglycan.

Child↗
PubMed2006

Zeta-sarcoglycan is a functional homologue of gamma-sarcoglycan in the formation of the sarcoglycan complex.

The sarcoglycans (SGs), transmembrane components of the dystrophin-associated glycoprotein complex, are stable and functional only when they assemble into a tetrameric complex in muscle cells. A defect in any one of the four SG members disrupts the entire SG complex (SGC) and causes limb-girdle muscular dystrophy. zeta-SG has been recently found as a transmembrane protein homologous to gamma-SG and delta-SG. To characterize zeta-SG in complex formation, we co-transfected expression vectors encoding all six SGs (alpha-, beta-, gamma-, delta-, epsilon- and zeta-SG) and dystroglycan into Chinese hamster ovary cells. Immunoprecipitation analysis showed that zeta-SG or gamma-SG formed a SGC with beta-SG and delta-SG plus alpha-SG or epsilon-SG, revealing that zeta-SG can form two types of SGCs (alpha-beta-zeta-delta or epsilon-beta-zeta-delta). This result indicates the functional resemblance of zeta-SG to gamma-SG rather than delta-SG, although phylogenetic analysis suggests that zeta-SG is evolutionally closer to delta-SG than to gamma-SG. Reverse transcription (RT)-PCR showed that the expression pattern of the transcript was almost the reciprocal of that of gamma-SG in various mouse tissues and that the zeta-SG transcript was especially abundant in the brain, suggesting that zeta-SG might play a particular role in the central nervous system.

Animals↗
PubMed1999

epsilon-sarcoglycan replaces alpha-sarcoglycan in smooth muscle to form a unique dystrophin-glycoprotein complex.

The sarcoglycan complex has been well characterized in striated muscle, and defects in its components are associated with muscular dystrophy and cardiomyopathy. Here, we have characterized the smooth muscle sarcoglycan complex. By examination of embryonic muscle lineages and biochemical fractionation studies, we demonstrated that epsilon-sarcoglycan is an integral component of the smooth muscle sarcoglycan complex along with beta- and delta-sarcoglycan. Analysis of genetically defined animal models for muscular dystrophy supported this conclusion. The delta-sarcoglycan-deficient cardiomyopathic hamster and mice deficient in both dystrophin and utrophin showed loss of the smooth muscle sarcoglycan complex, whereas the complex was unaffected in alpha-sarcoglycan null mice in agreement with the finding that alpha-sarcoglycan is not expressed in smooth muscle cells. In the cardiomyopathic hamster, the smooth muscle sarcoglycan complex, containing epsilon-sarcoglycan, was fully restored following intramuscular injection of recombinant delta-sarcoglycan adenovirus. Together, these results demonstrate a tissue-dependent variation in the sarcoglycan complex and show that epsilon-sarcoglycan replaces alpha-sarcoglycan as an integral component of the smooth muscle dystrophin-glycoprotein complex. Our results also suggest a molecular basis for possible differential smooth muscle dysfunction in sarcoglycan-deficient patients.

Animals↗
PubMed2001

Overexpression of gamma-sarcoglycan induces severe muscular dystrophy. Implications for the regulation of Sarcoglycan assembly.

The sarcoglycan complex is found normally at the plasma membrane of muscle. Disruption of the sarcoglycan complex, through primary gene mutations in dystrophin or sarcoglycan subunits, produces membrane instability and muscular dystrophy. Restoration of the sarcoglycan complex at the plasma membrane requires reintroduction of the mutant sarcoglycan subunit in a manner that will permit normal assembly of the entire sarcoglycan complex. To study sarcoglycan gene replacement, we introduced transgenes expressing murine gamma-sarcoglycan into muscle of normal mice. Mice expressing high levels of gamma-sarcoglycan, under the control of the muscle-specific creatine kinase promoter, developed a severe muscular dystrophy with greatly reduced muscle mass and early lethality. Marked gamma-sarcoglycan overexpression produced cytoplasmic aggregates that interfered with normal membrane targeting of gamma-sarcoglycan. Overexpression of gamma-sarcoglycan lead to the up-regulation of alpha- and beta-sarcoglycan. These data suggest that increased gamma-sarcoglycan and/or mislocalization of gamma-sarcoglycan to the cytoplasm is sufficient to induce muscle damage and provides a new model of muscular dystrophy that highlights the importance of this protein in the assembly, function, and downstream signaling of the sarcoglycan complex. Most importantly, gene dosage and promoter strength should be given serious consideration in replacement gene therapy to ensure safety in human clinical trials.

Animals↗
PubMed2002

Zeta-sarcoglycan, a novel component of the sarcoglycan complex, is reduced in muscular dystrophy.

The dystrophin glycoprotein complex (DGC) is found at the plasma membrane of muscle cells, where it provides a link between the cytoskeleton and the extracellular matrix. A subcomplex within the DGC, the sarcoglycan complex, associates with dystrophin and mediates muscle membrane stability. Mutations in sarcoglycan genes lead to muscular dystrophy and cardiomyopathy in both humans and mice. In invertebrates, there are three sarcoglycan genes, while in mammals there are additional sarcoglycan genes that probably arose from gene duplication events. We identified a novel mammalian sarcoglycan, zeta-sarcoglycan, that is highly related to gamma-sarcoglycan and delta-sarcoglycan. We generated a zeta-sarcoglycan-specific antibody and found that zeta-sarcoglycan associated with other members of the sarcoglycan complex at the plasma membrane. Additionally, zeta-sarcoglycan was reduced at the membrane in muscular dystrophy, consistent with a role in mediating membrane stability. zeta-Sarcoglycan was also found as a component of the vascular smooth muscle sarcoglycan complex. Together, these data demonstrate that zeta-sarcoglycan is an integral component of the sarcoglycan complex and, as such, is important in the pathogenesis of muscular dystrophy.

Amino Acid Sequence↗
PubMed2000

Expression of gamma -sarcoglycan in smooth muscle and its interaction with the smooth muscle sarcoglycan-sarcospan complex.

The sarcoglycan complex in striated muscle is a heterotetrameric unit integrally associated with sarcospan in the dystrophin-glycoprotein complex. The sarcoglycans, alpha, beta, gamma, and delta, are mutually dependent with regard to their localization at the sarcolemma, and mutations in any of the sarcoglycan genes lead to limb-girdle muscular dystrophies type 2C-2F. In smooth muscle beta- and delta-sarcoglycans are associated with epsilon-sarcoglycan, a glycoprotein homologous to alpha-sarcoglycan. Here, we demonstrate that gamma-sarcoglycan is also a component of the sarcoglycan complex in the smooth muscle. First, we show the presence of gamma-sarcoglycan in a number of smooth muscle-containing organs, and we verify the existence of identical transcripts in skeletal and smooth muscle. The specificity of the expression of gamma-sarcoglycan in smooth muscle was confirmed by analysis of smooth muscle cells in culture. Next, we provide evidence for the association of gamma-sarcoglycan with the sarcoglycan-sarcospan complex by biochemical analysis and comparison among animal models for muscular dystrophy. Moreover, we find disruption of the sarcoglycan complex in the vascular smooth muscle of a patient with gamma-sarcoglycanopathy. Taken together, our results prove that the sarcoglycan complex in vascular and visceral smooth muscle consists of epsilon-, beta-, gamma-, and delta-sarcoglycans and is associated with sarcospan.

Amino Acid Sequence↗
PubMed1999

Loss of the sarcoglycan complex and sarcospan leads to muscular dystrophy in beta-sarcoglycan-deficient mice.

beta-Sarcoglycan, one of the subunits of the sarcoglycan complex, is a transmembranous glycoprotein which associates with dystrophin and is the molecule responsible for beta-sarcoglycanopathy, a Duchenne-like autosomal recessive muscular dystrophy. To develop an animal model of beta-sarcoglycanopathy and to clarify the role of beta-sarcoglycan in the pathogenesis of the muscle degeneration in vivo, we developed beta-sarcoglycan-deficient mice using a gene targeting technique. beta-Sarcoglycan-deficient mice (BSG(-)(/-)mice) exhibited progressive muscular dystrophy with extensive degeneration and regeneration. The BSG(-)(/-)mice also exhibited muscular hypertrophy characteristic of beta-sarcoglycanopathy. Immunohistochemical and immunoblot analyses of BSG(-)(/-)mice demonstrated that deficiency of beta-sarcoglycan also caused loss of all of the other sarcoglycans as well as of sarcospan in the sarcolemma. On the other hand, laminin-alpha2, alpha- and beta-dystroglycan and dystrophin were still present in the sarcolemma. However, the dystrophin-dystroglycan complex in BSG(-)(/-)mice was unstable compared with that in the wild-type mice. Our data suggest that loss of the sarcoglycan complex and sarcospan alone is sufficient to cause muscular dystrophy, that beta-sarcoglycan is an important protein for formation of the sarcoglycan complex associated with sarcospan and that the role of the sarcoglycan complex and sarcospan may be to strengthen the dystrophin axis connecting the basement membrane with the cytoskeleton.

Animals↗
PubMed2000

Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by beta sarcoglycan mutations.

Two young males with limb-girdle muscular dystrophy (LGMD) resulting from sarcoglycan deficiency died at 27 (patient 1) and 18 years (patient 2) of severe cardiomyopathy. Genetic analysis showed that they were compound heterozygotes for mutations in the beta sarcoglycan gene. One of these mutations, an 8 bp duplication in exon 3, was common to both patients. The second mutation in patient 2 was a 4 bp deletion at the splice donor site of intron 2, not reported previously. Patient 2 had more severe heart and skeletal muscle defects with faster deterioration; no sarcoglycans were detected in his skeletal muscle. The second mutation in patient 1, inferred because the unaffected father carries the 8 bp duplication, was not found. In patient 1, both heart and skeletal muscle were analysed and showed reduction of all sarcoglycans in both tissues and incorrect localisation of alpha and gamma sarcoglycans in heart. Therefore mutations in one sarcoglycan gene can disrupt the entire sarcoglycan complex in both skeletal and cardiac muscle. Differing expression patterns of sarcoglycan components in heart and skeletal muscle could be the result of alternatively spliced transcripts in these tissues. By sequencing an alternative transcript, highly expressed in the heart and skeletal muscle of patient 1, we found an 87 bp cryptic exon not previously reported. Although cardiomyopathy can result from mutations in alpha and gamma sarcoglycans, we show for the first time that the condition can also be caused by mutations in the beta sarcoglycan gene. This report therefore expands the phenotype of sarcoglycanopathies and suggests that cardiac function in LGMD patients with defective sarcoglycan expression should be monitored.

Adolescent↗
PubMed1997

Concomitant deficiency of beta- and gamma-sarcoglycans in 20 alpha-sarcoglycan (adhalin)-deficient patients: immunohistochemical analysis and clinical aspects.

We have investigated the expression, using immunohistochemistry, of beta- and gamma-sarcoglycans in the muscles of 20 patients in whom previous screening had revealed a deficiency of alpha-sarcoglycan. alpha-, beta- and gamma-sarcoglycans were absent in 7 patients and variably reduced in 8 patients, in 2 of whom beta-sarcoglycan was more reduced than the alpha- and gamma-proteins. In 5 other patients with variably reduced alpha- and beta-sarcoglycans, gamma-sarcoglycan was completely absent. In all patients the distribution of hyposthenia at disease onset was similar, and predominantly involved pelvic girdle muscles; however, the age at onset and rate of disease progression were highly variable. In severely compromised patients, the onset of disease was before 10 years of age and gamma-sarcoglycan or all three sarcoglycans were absent from muscles. Immunohistochemical analysis of sarcoglycans should be part of routine screening for muscle dystrophies to identify patients with sarcoglycanopathy. Gene analysis is necessary to identify the primary defect; however, sarcoglycan immunohistochemistry may be useful for indicating which gene to investigate. Further biochemical characterization of the interactions between these proteins is required to fully elucidate their roles in causing severe, moderate or mild muscular dystrophy.

Adolescent↗
PubMed1998

Functional rescue of the sarcoglycan complex in the BIO 14.6 hamster using delta-sarcoglycan gene transfer.

Four types of limb-girdle muscular dystrophy (LGMD) are known to be caused by mutations in distinct sarcoglycan genes. The BIO 14.6 hamster is a model for sarcoglycan-deficient LGMD with a deletion in the delta-sarcoglycan (delta-SG) gene. We investigated the function of the sarcoglycan complex and the feasibility of sarcoglycan gene transfer for LGMD using a recombinant delta-SG adenovirus in the BIO 14.6 hamster. We demonstrate extensive long-term expression of delta-sarcoglycan and rescue of the entire sarcoglycan complex, as well as restored stable association of alpha-dystroglycan with the sarcolemma. Importantly, muscle fibers expressing delta-sarcoglycan lack morphological markers of muscular dystrophy and exhibit restored plasma membrane integrity. In summary, the sarcoglycan complex is requisite for the maintenance of sarcolemmal integrity, and primary mutations in individual sarcoglycan components can be corrected in vivo.

Adenoviridae↗
PubMed1998

Human epsilon-sarcoglycan is highly related to alpha-sarcoglycan (adhalin), the limb girdle muscular dystrophy 2D gene.

The dystrophin-glycoprotein complex (DGC) is critical for muscle membrane stability. The sarcoglycans are transmembrane proteins within the DGC, and the function of the sarcoglycans is unknown. Mutations in sarcoglycan genes cause autosomal recessive muscular dystrophy. We have identified a new sarcoglycan gene with high homology to alpha-sarcoglycan highlighting the redundancy of the DGC. This gene, named epsilon-sarcoglycan, has an identical intron-exon structure to alpha-sarcoglycan, and is more broadly expressed. The characterization of epsilon-sarcoglycan should make it possible to determine if it, like the other sarcoglycan genes, is mutated in muscular dystrophy.

Alleles↗
PubMed1997

New missense mutation in the alpha-sarcoglycan gene in a Japanese patient with severe childhood autosomal recessive muscular dystrophy with incomplete alpha-sarcoglycan deficiency.

A new homozygous alpha-sarcoglycan (adhalin) gene mutation was found in a Japanese patient with severe childhood autosomal recessive muscular dystrophy (SCARMD). Muscle biopsy specimens from the patient showed marked reduction but not complete deficiency of alpha-sarcoglycan. The sequence of part of exon 3 of the alpha-sarcoglycan gene exhibited a cytosine to thymidine substitution at nucleotide position 220. Since the same mutation was not found in 100 normal control samples, this new alpha-sarcoglycan gene mutation is not a polymorphism but is presumed to be responsible for the marked reduction of alpha-sarcoglycan in skeletal muscle. Most patients with homozygous alpha-sarcoglycan gene mutation were reported to show complete alpha-sarcoglycan deficiency. Present case showed the homozygous missense mutation of alpha-sarcoglycan and associated with incomplete alpha-sarcoglycan deficiency and severe clinical phenotype.

Action Potentials↗
PubMed1996

Characterization of delta-sarcoglycan, a novel component of the oligomeric sarcoglycan complex involved in limb-girdle muscular dystrophy.

The sarcoglycan complex is known to be involved in limb-girdle muscular dystrophy (LGMD) and is composed of at least three proteins: alpha-, beta-, and gamma-sarcoglycan. delta-Sarcoglycan has now been identified as a second 35-kDa sarcolemmal transmembrane glycoprotein that shares high homology with gamma-sarcoglycan and is expressed mainly in skeletal and cardiac muscle. Biochemical analysis has demonstrated that gamma- and delta-sarcoglycan are separate entities within the sarcoglycan complex and that all four sarcoglycans exist in the complex on a stoichiometrically equal basis. Immunohistochemical analysis of skeletal muscle biopsies from patients with LGMD2C, LGMD2D, and LGMD2E demonstrated a reduction of the entire sarcoglycan complex in these muscular dystrophies. Furthermore, we have mapped the human delta-sarcoglycan gene to chromosome 5q33-q34 in a region overlapping the recently linked autosomal recessive LGMD2F locus.

Amino Acid Sequence↗
PubMed2004

Specific assembly pathway of sarcoglycans is dependent on beta- and delta-sarcoglycan.

Mutations in sarcoglycans (SG) have been reported to cause autosomal-recessive limb-girdle muscular dystrophy (LGMD) and dilated cardiomyopathy. In skeletal and cardiac muscle, sarcoglycans exist as a complex of four transmembrane proteins (alpha-, beta-, gamma-, and delta-SG). In this study, the assembly of the sarcoglycan complex was examined in a heterologous expression system. Our results demonstrated that the assembly process occurs as a discrete stepwise process. We found that beta-SG appears to play an initiating role and its association with delta-SG is essential for the proper localization of the sarcoglycan complex to the cell membrane. The incorporation of alpha-SG into the sarcoglycan complex occurs at the final stage by interaction with gamma-SG. These findings were supported by chemical cross-linking of endogenous sarcoglycans in cultured myotubes. We have also provided evidence that glycosylation-defective mutations in beta-SG and a common mutation in gamma-SG (C283Y) disrupt sarcoglycan-complex formation. Our proposed model for the assembly and structure of sarcoglycans should generate important insight into their function in muscle as well as their role in muscular dystrophies and cardiomyopathies.

Animals↗
PubMed1995

Beta-sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex.

The dystrophin associated proteins (DAPs) are good candidates for harboring primary mutations in the genetically heterogeneous autosomal recessive muscular dystrophies (ARMD). The transmembrane components of the DAPs can be separated into the dystroglycan and the sarcoglycan complexes. Here we report the isolation of cDNAs encoding the 43 kD sarcoglycan protein beta-sarcoglycan (A3b) and the localization of the human gene to chromosome 4q12. We describe a young girl with ARMD with truncating mutations on both alleles. Immunostaining of her muscle biopsy shows specific loss of the components of the sarcoglycan complex (beta-sarcoglycan, alpha-sarcoglycan (adhalin), and 35 kD sarcoglycan). Thus secondary destabilization of the sarcoglycan complex may be an important pathophysiological event in ARMD.

Amino Acid Sequence↗
PubMed2001

Extraocular muscle is spared despite the absence of an intact sarcoglycan complex in gamma- or delta-sarcoglycan-deficient mice.

Models of the dystrophin-glycoprotein complex do not reconcile the novel sparing of extraocular muscle in muscular dystrophy. Extraocular muscle sparing in Duchenne muscular dystrophy implies the existence of adaptive properties in these muscles that may extend protection to other neuromuscular diseases. We studied the extraocular muscle morphology and dystrophin-glycoprotein complex organization in murine targeted deletion of the gamma-sarcoglycan (gsg(-/-)) and delta-sarcoglycan (dsg(-/-)) genes, two models of autosomal recessive limb girdle muscular dystrophy. In contrast to limb and diaphragm, the principal extraocular muscles were intact in gsg(-/-) and dsg(-/-) mice. However, central nucleated, presumptive regenerative, fibers were seen in the accessory extraocular muscles (retractor bulbi, levator palpebrae superioris) of both strains. Skeletal muscles of gsg(-/-) mice exhibited in vivo Evans Blue dye permeability, while the principal extraocular muscles did not. Disruption of gamma-sarcoglycan produced secondary displacement of alpha- and beta-sarcoglycans in the extraocular muscles. The intensity of immunofluorescence for dystrophin and alpha- and beta-dystroglycan also appeared to be slightly reduced. Utrophin localization was unchanged. The finding that sarcoglycan disruption was insufficient to elicit alterations in extraocular muscle suggests that loss of mechanical stability and increased sarcolemmal permeability are not inevitable consequences of mutations that disrupt the dystrophin-glycoprotein complex organization and must be accounted for in models of muscular dystrophy.

Animals↗
PubMed1997

Absence of alpha-sarcoglycan and novel missense mutations in the alpha-sarcoglycan gene in a young British girl with muscular dystrophy.

An 11-year-old white female presented with progressive proximal muscle weakness and marked calf hypertrophy. Muscle biopsy showed severe dystrophy with normal expression of dystrophin. There was complete absence of the 50kDa dystrophin-associated glycoprotein (alpha-sarcoglycan). DNA analysis showed novel point mutations (one missense and one splicing) in the alpha-sarcoglycan gene at chromosomal location 17q21, confirming the diagnosis of limb-girdle muscular dystrophy type 2D (LGMD-2D). We believe this is one of the first confirmed white cases of primary alpha-sarcoglycanopathy identified in the UK. This case supports the assumption of a wide geographic prevalence of severe childhood onset autosomal recessive muscular dystrophy and genetic heterogeneity. In the future, with improved diagnostic accuracy it is likely that more cases demonstrating primary or secondary deficiency of alpha-sarcoglycan will be identified. We would recommend staining for dystrophin-associated glycoproteins (sarcoglycans) in all new cases of muscular dystrophy with normal dystrophin, and confirmation with DNA analysis where possible.

Biopsy↗
PubMed2006

Alpha-sarcoglycan is recycled from the plasma membrane in the absence of sarcoglycan complex assembly.

The sarcoglycan complex consists of four subunits in skeletal muscle (alpha, beta, gamma, and delta-SG). Mutations in alpha-sarcoglycan (alpha-SG) result in the most common form of limb girdle muscular dystrophy. However, the function of alpha-SG remains unknown. In this report we attempt to clarify its function by delineating the trafficking pathway of alpha-SG in live cells. We present evidence, utilizing total internal reflection microscopy, fluorescence recovery after photobleaching and photoactivation of green fluorescent protein (GFP) constructs, that pools of alpha-SG are able to translocate to the plasma membrane in the absence of the remaining sarcoglycans. Internalization assays and drug treatment experiments demonstrate that alpha-SG recycles from the plasma membrane and accumulates in recycling endosomes. We also establish that alpha-SG utilizes well-described clathrin mediated mechanisms and microtubules to traffic within the cell. Finally, we show that the most commonly reoccurring limb girdle muscular dystrophy (R77C) mutation causes a fundamental defect in protein biosynthesis, trapping the mutant protein in the endoplasmic recticulum (ER). These results demonstrate that alpha-SG requires assembly into the sarcoglycan complex for stability at the plasma membrane rather than export out of the ER. Furthermore, this data suggests that alpha-SG utilizes known trafficking machinery to control deposition at the plasma membrane through recycling.

Arginine↗