Mutations in the δ-sarcoglycan gene are a rare cause of autosomal recessive limb-girdle muscular dystrophy (LGMD2)

The dystrophin-based membrane cytoskeleton of muscle fibers has emerged as a critical multiprotein complex which seems to impart structural integrity on the muscle fiber plasma membrane. Deficiency of dystrophin causes the most common types of muscular dystrophy, Duchenne and Becker muscular dystrophies. Muscular dystrophy patients showing normal dystrophin protein and gene analysis are generally isolated cases with a presumed autosomal recessive inheritance pattern (limb-girdle muscular dystrophy). Recently, linkage and candidate gene analyses have shown that some cases of limb-girdle muscular dystrophy can be caused by deficiency of other components of the dystrophin membrane cytoskeleton. The most recently identified component, δ-sarcoglycan deficiency occurred in other world populations, to identify the range of mutations and clinical phenotypes, and to test for the biochemical consequences of δ-sarcoglycan gene mutations, we studied Duchenne-like and limb-girdle muscular dystrophy patients who we had previously shown not to exhibit gene mutations of dystrophin, α-, β-, or γ-sarcoglycan for δ-sarcoglycan mutations (n = 54). We identified two American patients with novel nonsense mutations of δ-sarcoglycan (W30X, R165X). One was apparently homozygous, and we show likely consanguinity through homozygosity for 13 microsatellite loci covering a 38 cM region of chromosome 5. The second was heterozygous. Both were girls who showed clinical symptoms consistent with Duchenne muscular dystrophy in males. Our data shows that δ-sarcoglycan deficiency occurs in other world populations, and that most or all patients show a deficiency of the entire sarcoglycan complex, adding support to the hypothesis that these proteins function as a tetrameric unit. Received January 1, 1997; Revised and Accepted January 15, 1997     

Sarcoglycanopathy]

Sarcoglycanopathy is a group of four autosomal recessive muscular dystrophies whose symptoms are similar to Duchenne muscular dystrophy (DMD). These dystrophies are caused by mutations on anyone of the genes encoding four subunits of sarcoglycan complex which are transmembranous and dystrophin associated proteins. When the protein product of the mutated gene is absent, entire sarcoglycan complex is absent or greatly reduced in amount. This further gives rise to the weak connection between dystrophin and dystroglycan complex. These cause Duchenne-like phenotype. In DMD, dystrophin is absent and sarcoglycan complex is greatly reduced. These similarities in molecular defects in these diseases may cause the similarity in symptoms.     

Sarcolemmal Alpha and Gamma Sarcoglycan Protein Deficiencies in Turkish Siblings With a Novel Missense Mutation in the Alpha Sarcoglycan Gene

BackgroundThe sarcoglycan alpha gene, also known as the adhalin gene, is located on chromosome 17q21; mutations in this gene are associated with limb-girdle muscular dystrophy type 2D. We describe two Turkish siblings with findings consistent with limb-girdle muscular dystrophy type 2D. The evaluation excluded a dystrophinopathy, which is the most common form of muscular dystrophy.PatientsBoth siblings had very high levels of creatinine phosphokinase and negative molecular tests for deletions and duplications of the dystrophin gene. The older boy presented at 8 years of age with an inability to climb steps and an abnormal gait. His younger brother was 5 years old and had similar symptoms. The muscle biopsy evaluation was performed only in the older brother.ResultsThe muscle biopsy showed dystrophic features as well as a deficiency in the expression of two different glycoproteins: the alpha sarcoglycan and the gamma sarcoglycan. Sarcolemmal expressions of dystrophin and other sarcoglycans (beta and delta) were diffusely present. DNA analysis demonstrated the presence of previously unknown homozygous mutations [c.226 C > T (p.L76 F)] in exon 3 in the sarcoglycan alpha genes of both siblings. Similar heterozygous point mutations at the same locus were found in both parents, but the genes of beta, delta, and gamma sarcoglycan were normal in the remaining family members.ConclusionsWe describe two siblings with limb-girdle muscular dystrophy type 2D with a novel missense mutation. These patients illustrate that the differential diagnosis of muscular dystrophies is impossible with clinical findings alone. Therefore, a muscle biopsy and DNA analysis remain essential methods for diagnosis of muscle diseases.     

Molecular diagnosis of muscular dystrophies

Dystrophin, the protein product of the DMD/BMD (Duchenne muscular dystrophy/Becker muscular dystrophy) gene, is associated with dystrophin-associated proteins (DAPs), which are classified into three groups: the dystroglycan complex, the sarcoglycan complex and the syntrophin complex. There is a connecting axis between subsarcolemmal actin filaments and laminin, one of the main components of the extracellular matrix through dystrophin and dystroglycan. This system may play an important role in protecting the sarcolemma during contraction and relaxation of muscle fibers. In this paper, the abnormalities of DAPs and laminin as a cause of muscular dystrophies are reviewed. While there are no reports on the role of mutations of dystroglycan and the syntrophin gene as being a cause of muscular dystrophies, the immunostaining intensities of these complexes are reduced as a secondary phenomenon of defects of dystrophin in DMD. The sarcoglycan complex, which is comprised of membrane-integrated proteins, contains at least four components, each of which is encoded by a separate gene. This complex plays a crucial role in the development of severe childhood autosomal recessive muscular dystrophy (SCARMD). In this disease, the absence of any single component may result in a loss of the complex function. Therefore, SCARMD develops irrespective of any mechanism involving a defect of individual genes. As such SCARMD is collectively referred to as sarcoglycanopathy. Laminin, a heterotrimer and genetic defect of the α2 subunit, has been shown to be the cause of the classical type of congenital muscular dystrophy. This disease is characterized by floppy infants with severe muscular dystrophy, dysmyelinating neuropathy and white matter changes in the brain. In the clinical setting and in the mouse model of this disease a defect of the laminin α2 subunit in skeletal muscle has been demonstrated. α2 subunit-null mutant mice also exhibit the muscular dystrophy phenotype and a muscle pathology compatible with dystrophia muscularis (dy) mice. A final common mechanism of muscle-cell necrosis in many of the muscular dystrophies is associated with the destabilization of the sarcolemma.     

Primary adhalin deficiency as a cause of muscular dystrophy in patients with normal dystrophin

In our experience, more than half of muscular dystrophy patients show a primary dystrophinopathy. The underlying cause of muscular dystrophy in the vast majority of patients with normal dystrophin is unknown. Recently, a French family with 4 young siblings showing a muscular dystrophy of unknown progression was shown to have a primary deficiency of ?adhalin,”? the 50-kd dystrophin-associated protein. Here we report the screening of the entire adhalin coding sequence in muscle biopsy specimens from 30 muscular dystrophy patients to (1) determine whether adhalin deficiency is restricted to the French population, (2) determine the incidence of adhalin deficiency in muscular dystrophy patients, and (3) characterize the clinical features and mutations in adhalin-deficient patients. We identified a single African-American girl with childhood-onset muscular dystrophy and adhalin gene mutations. We found her to be a compound heterozygote for two different mutations of the same amino acid (Arg98Cys; Arg98His), one of which was previously identified in the French family. Our results suggest that primary adhalin deficiency in patients with muscular dystrophy but normal dystrophin is relatively infrequent, and that adhalin-deficient patients are not restricted to the French population.     

Sarcoglycanopathies: can muscle immunoanalysis predict the genotype?

Muscle immunoanalysis of the sarcoglycan complex is an important part of the diagnostic evaluation of muscle biopsies in patients with autosomal recessive limb-girdle muscular dystrophy. Reduced or absent sarcolemmal expression of one or all of the four sarcoglycans (alpha-, beta-, gamma-, delta-sarcoglycan) can be found in patients with limb-girdle muscular dystrophy 2C-F (LGMD2C-F) and also in patients with Duchenne and Becker muscular dystrophy (DMD/BMD). It has previously been suggested that different patterns of sarcoglycan expression could predict the primary genetic defect, and that genetic analysis could be directed by these patterns. In this first UK study we studied 24 genetically characterized patients with sarcoglycan deficient LGMD, in 22 of whom muscle immunoanalysis data were available. Thirteen patients showed alpha-sarcoglycan deficient LGMD2D, 7 patients beta-sarcoglycan deficient LGMD2E, 3 patients gamma-sarcoglycan deficient LGDM2C, and one patient delta-sarcoglycan deficient LGMD2F. Muscle biopsies were analysed in one centre without knowledge of the established genetic diagnosis. Our results demonstrated that residual sarcoglycan expression is highly variable and does not enable an accurate prediction of the genotype. Considering previous reports of sarcoglycanopathy patients with an isolated loss of one sarcoglycan we recommend to use antibodies against all four sarcoglycans for immunoanalysis of skeletal muscle sections. A concomitant reduction of dystrophin and beta-dystroglycan was observed more frequently than previously reported and illustrates the important differential diagnosis of DMD and BMD for sarcoglycan deficient LGMD.     

Cardiomyopathic features associated with muscular dystrophy are independent of dystrophin absence in cardiovasculature

The loss of dystrophin results in skeletal muscle degeneration and cardiomyopathy in patients with Duchenne muscular dystrophy. In skeletal muscle, dystrophin strengthens the myofiber membrane by linking the submembranous cytoskeleton and extracellular matrix through its direct interaction with the dystroglycan/sarcoglycan complex. In limb-girdle muscular dystrophy, the loss of the sarcoglycans in cardiovasculature leads to cardiomyopathy. It is unknown whether the absence of dystrophin in cardiomyocytes or cardiovasculature leads to the cardiomyopathy associated with primary dystrophin deficiency. We show here that the cardiomyopathic features of the utrophin/dystrophin-deficient mouse can be prevented by the presence of dystrophin in cardiomyocytes but not in cardiovasculature. Furthermore, restoration of the dystroglycans and sarcoglycans to the cardiomyocyte membrane is not sufficient to prevent cardiomyopathy. These data provide the first evidence that dystrophin plays a mechanical role in cardiomyocytes similar to its role in skeletal muscle. These results indicate that treatment of cardiomyocytes but not cardiovasculature is essential in dystrophinopathies.     

Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7% of the patients, deletions were found in at least one of the exons; 68% of these deletions were in the hot-spot 3' region. Deletions were found in 81.5% of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains). The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.     

Functional roles of dystrophin and of associated proteins. New insights for the sarcoglycans

The discovery of the dystrophin gene, whose mutations lead to Duchenne's and Becker's muscular dystrophy (DMD and BMD), represents the first important landmark by which, in the last ten years, molecular biology and genetic studies have revealed many of the molecular defects of the major muscular dystrophies. Very rapidly, several studies revealed the presence at skeletal and cardiac muscle sarcolemma of a group of proteins associated to dystrophin. This includes a set of five transmembrane glycoproteins, the sarcoglycans, whose physiological role, however, is still poorly understood. Dystrophin and the associated proteins are believed to play an important role in membrane stability and maintenance during muscle contraction and relaxation. However, the absence of sarcoglycans from sarcolemma does not appear to affect membrane integrity suggesting that these components of the dystrophin complex are recipients of other important functions. This review deals with recent advances in the knowledge of sarcoglycan function and organization that may give important insights into the pathogenetic mechanisms of muscular dystrophies.     

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.     

Partial alpha-sarcoglycan deficiency with retention of the dystrophin-glycoprotein complex in a LGMD2D family

In patients with sarcoglycan (SG) deficiency, a primary defect in any one of the four SG proteins usually leads to reduced expression of the whole SG complex. We report a limb-girdle muscular dystrophy type 2D family (LGMD2D), with variable phenotype, where a mutation in the alpha-SG gene resulted in the partial deficiency of alpha-SG alone. The normal expression of the other three SG proteins suggests that mutations close to the alpha-SG transmembrane domain might be less critical for complex integrity, and that weakness may occur despite its retention.     

Muscular dystrophy: advances in research works and therapeutic trials]

Muscular dystrophy is defined as "a group of hereditary disorders with the major symptom of progressive muscle weakness due to muscle fiber degeneration and necrosis". After the discovery of the dystrophin gene and the gene product for Duchenne muscular dystrophy in 1986, there has been remarkable progress in the differential diagnosis and in understanding the pathogenetic mechanism of muscle fiber necrosis. With discoveries of genes responsible for many other disorders, the classification of muscular dystrophy has become more complicated; for instance, there are at least 15 diseases in the limb-girdle muscular dystrophy (LGMD) group, including the autosomal dominant forms, LGMD1A-1E and the recessive forms, LGMD2A-2I. Among them, gene defects in the sarcoglycan complex (sarcoglycanopathy) have been added to LGMD2C-2F. Sarcoglycanopathy seems to be rare in Japan since only 6-7% of LGMD patients had this defect. There are two major possible strategies in treating these patients. One is gene therapy, which is recently being investigated in the mdx mouse by using adenovirus-associated virus (AAV) vector inserted with a microdystrophin gene. Dr Takeda has reported favorable results in mdx mouse muscle with this method. Another is regeneration therapy using stem cells. There are many barriers to overcome to treat patients with stem cells isolated from bone marrow. The most difficult problem to solve is how to culture the stem cells to increase their numbers for application and how to introduce the normal dystrophin gene into these cells.     

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.     

α-Sarcoglycan (adhalin) deficiency: complete deficiency patients are 5% of childhood-onset dystrophin-normal muscular dystrophy and most partial deficiency patients do not have gene mutations

α-Sarcoglycan (adhalin), a 50-kDa component of the dystrophin-associated complex of proteins, participates in the stabilization of the myofiber plasma membrane in the membrane cytoskeleton. Deficiencies of α-sarcoglycan cause a subset of childhood-onset muscular dystrophy (SCARMD) cases. However, secondary deficiencies of α-sarcoglycan are common. To begin to establish the rates of false positives (secondary deficiencies), we used immunofluorescence to screen 30 Italian dystrophin-normal muscular dystrophy patient biopsies and identified 4 patients with partial α-sarcoglycan deficiency and 2 patients with complete deficiency. The entire α-sarcoglycan gene was screened for mutations using RT-PCR and SSCP of messenger RNA isolated from muscle biopsies in each of the six patients. Aberrant SSCP conformers and novel mutations were found only in the two complete immunohistochemical deficient patients. One patient was homozygous for a R34H amino acid substitution, while the other was a compound heterozygote (R77C, D97G). These three missense mutations, with additional mutations we and others have previously described, are all localized in the extracellular domain of α-sarcoglycan, and most result in the loss or gain of a positively charged amino acid. These data have strong implications for structure/function maps of the α-sarcoglycan molecule. Our results suggest that most patients showing partial α-sarcoglycan deficiency exhibit this as a secondary consequence of genetically distinct disorders. In support of this, we show biochemical data indicating that secondary deficiency patients show decreased immunostaining with antibodies directed against α-sarcoglycan, while having nearly normal quantities of α-sarcoglycan protein on immunoblot. This data also suggests that approximately 5% of childhood-onset dystrophin-normal muscular dystrophy patients will show a primary α-sarcoglycan deficiency.     

Abnormalities in α-, β- and γ-sarcoglycan in patients with limb-girdle muscular dystrophy

We have identified 12 cases from a group of 45 patients with early onset limb-girdle muscular dystrophy (LGMD), who have a deficiency of the 50 kDa dystrophin-associated glycoprotein, α-sarcoglycan. An additional male sibling of one case was also studied clinically. All 12 patients showed a concomitant, but variable, deficiency of α-, β- and γ-sarcoglycan. None of our patients had a defect in only one component of the sarcoglycan complex. Molecular analysis confirmed that a total absence of one sarcoglycan, associated with reduced expression of the other two, indicates a primary defect. Immunocytochemistry is thus useful for directing molecular studies. Morphological features not usually observed in Xp21 dystrophies were peripheral accumulations of mitochondria, discrete core-like areas, and nemaline rods in one case. Clinical severity and progression was variable between and within families but early loss of ambulation, at or before the age of 12 years, was associated with a total absence of γ-sarcoglycan. Common clinical features were calf hypertrophy, contractures of the tendo achilles, lumbar lordosis, winging of the scapulae, weak hamstrings and weak neck muscles. All cases had grossly elevated serum creatine kinase. In contrast to patients with Duchenne muscular dystrophy (DMD), our patients with sarcoglycan deficiencies had normal early motor milestones, normal intellect, and good respiratory and cardiac function. Our data confirm that the sarcoglycan complex acts as a unit and that morphological and clinical features can distinguish patients with defects in the sarcoglycans from those with Xp21 dystrophy. In our group of patients prognosis is better than in DMD, but clinical variability makes this difficult to predict in isolated cases.     

Coexisting muscular dystrophies and epilepsy in children

Muscular dystrophies are composed of a variety of genetic muscle disorders linked to different chromosomes and loci and associated with different gene mutations that lead to progressive muscle atrophy and weakness. Fukuyama congenital muscular dystrophy is frequently associated with partial and generalized epilepsy and congenital brain anomalies, including cobblestone complex and other neuronal migration defects. We report generalized convulsive epilepsy in a boy with normal brain magnetic resonance imaging and Duchenne muscular dystrophy with deletion of dystrophin gene, and we report absence epilepsy with normal brain magnetic resonance imaging in another boy with limb girdle muscular dystrophy with partial calpain deficiency. We, therefore, review coexisting muscular dystrophies and epilepsy in children. In addition to Fukuyama congenital muscular dystrophy, partial or generalized epilepsy has also been reported in the following types of muscular dystrophies, including Duchenne/Becker dystrophy, facioscapulohumeral dystrophy, congenital muscular dystrophy with partial and complete deficiency of laminin alpha2 (merosin) chain, and limb girdle muscular dystrophy with partial calpain deficiency.     

Improved diagnosis of Becker muscular dystrophy by dystrophin testing

We assessed the quantity (relative cellular abundance) and quality (approximate molecular weight) of dystrophin in muscle biopsies from 97 patients with a diagnosis of possible Becker muscular dystrophy. Fifty-four (all male) had dystrophin abnormalities and were deemed to have true Becker muscular dystrophy. The other 43 patients (14 female, 29 male) had no detectable dystrophin abnormalities. Of the dystrophin-verified Becker dystrophy patients, 35% (19/54) had a family history consistent with X-linked recessive inheritance. On the other hand, none of the 43 patients with apparently normal dystrophin had a clear X-linked family history, suggesting that few of these 43 actually had a form of Becker dystrophy. The data suggest that of all patients with a clinical picture consistent with Becker dystrophy but no family history, about 60% will be true Becker patients. The correlation of both the biochemical and clinical data suggests that Duchenne/Becker dystrophy can be divided into 4 clinically useful categories: Duchenne dystrophy (wheelchair at about age 11 years; dystrophin quantity less than 3% of normal); severe Becker dystrophy (wheelchair age 13 to 20 years; dystrophin 3% to 10%); and moderate/mild Becker dystrophy (wheelchair greater than 20 years; dystrophin quantity greater than or equal to 20%). Given the observed clinical variability of Becker dystrophy, it appears that dystrophin analysis is required for accurately distinguishing between Becker dystrophy and clinically similar autosomal recessive myopathies.     

Pharmacological control of cellular calcium handling in dystrophic skeletal muscle

Duchenne muscular dystrophy arises due to the lack of the cytoskeletal protein dystrophin. In Duchenne muscular dystrophy muscle, the lack of dystrophin is accompanied by alterations in the dystrophin-glycoprotein complex. We and others have found that the absence of dystrophin in cells of the Duchenne muscular dystrophy animal model, the mdx mouse, leads to elevated Ca(2+) influx and cytosolic Ca(2+) concentrations when exposed to stress. We have also shown that alpha-methylprednisolone, the only drug used successfully in the therapy of Duchenne muscular dystrophy, and creatine lowered cytosolic Ca(2+) levels in mdx myotubes. It is likely that chronic elevation of [Ca(2+)] in the cytosol in response to stress is an initiating event for apoptosis and/or necrosis in Duchenne muscular dystrophy or mdx muscle and that alterations in mitochondrial function and metabolism are involved. Other cellular signalling pathways (e.g. nitric oxide) might also be affected.     

Correlative MR imaging and P-MR spectroscopy study in sarcoglycan deficient limb girdle muscular dystrophy

We combined magnetic resonance (MR) imaging and phosphorus magnetic resonance spectroscopy (³¹P-MRS) to study skeletal muscle in seven patients with limb girdle muscular dystrophy (LGMD) with a variable deficiency of the -, β-, and γ-sarcoglycan but normal dystrophin expression on muscle biopsy. T1- and T2-weighted spin-echo axial leg images showed the highest degree of fat replacement in soleus, tibialis anterior and peroneal muscles while gastrocnemius and tibialis posterior were less affected. In LGMD patients as a group, calf muscle phosphorylated compound content did not differ from controls, but the cytosolic pH was increased (P=0.02). The degree of calf muscle fat replacement correlated inversely with cytosolic pH (r=0.74) and directly with PCr/ATP (r=0.74). Muscle oxidative metabolism was normal in LGMD patients. Our findings show that primary deficits of sarcoglycan complex lead to specific morphological and metabolic patterns of skeletal muscle involvement.     

The beta-delta-core of sarcoglycan is essential for deposition at the plasma membrane

Mutations of any of the sarcoglycan complex subunits (alpha, beta, delta, and gamma) cause limb-girdle muscular dystrophy. Furthermore, individual mutations lead to a reduction or loss of all other members of the complex. In some cases of limb-girdle muscular dystrophies, however, residual sarcoglycan expression has been documented. Therefore, in this study we tested the hypothesis that formation of specific sarcoglycan subcomplexes is crucial for plasma membrane deposition. Using co-immunoprecipitation assays, we demonstrated that beta- and delta-sarcoglycan interact with alpha-sarcoglycan and these two subunits must be co-expressed for export from the endoplasmic reticulum. Advanced light-microscopic imaging techniques demonstrated that co-expression of beta-sarcoglycan and delta-sarcoglycan is also responsible for delivery to and retention of sarcoglycan subcomplexes at the cell surface. These data suggest that formation of the beta-delta-core may promote the export and deposition of sarcoglycan subcomplexes at the plasma membrane, and therefore identifies a mechanism for sarcoglycan transport.