Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder characterized by severe dystrophic muscle wasting from birth or early infancy with structural brain abnormalities. The gene for FCMD is located on chromosome 9q31, and encodes a novel protein named fukutin. The function of fukutin is not known yet, but is suggested to be an enzyme that modifies the cell-surface glycoprotein or glycolipids.
To elucidate the roles of fukutin gene mutation in skeletal and cardiac muscles and brain.
Immunohistochemical and immunoblot analyses were performed in skeletal and cardiac muscles and brain tissue samples from patients with FCMD and control subjects.
The authors found a selective deficiency of highly glycosylated alpha-dystroglycan, but not beta-dystroglycan, on the surface membrane of skeletal and cardiac muscle fibers in patients with FCMD. Immunoblot analyses also showed no immunoreactive band for alpha-dystroglycan, but were positive for beta-dystroglycan in FCMD in skeletal and cardiac muscles.
The current findings suggest a critical role for fukutin gene mutation in the loss or modification of glycosylation of the extracellular peripheral membrane protein, alpha-dystroglycan, which may cause a crucial disruption of the transmembranous molecular linkage of muscle fibers in patients with FCMD.
"Its aberrant glycosylation is associated with several congenital muscle diseases in humans, including Fukuyama-type congenital muscular dystrophy, muscle-eye-brain disease and Walker-Warburg syndrome (Barresi and Campbell 2006). Hyposialylation of the oligosaccharide chains of α-dystroglycan is their common pathological feature (Hayashi et al. 2001, Michele et al. 2002). The distorted glycosylation of the DGC component α-dystroglycan results in reduced binding to basal lamina components and loss in structural stability of muscle. "
[Show abstract][Hide abstract] ABSTRACT: The biology of sialic acids has been an object of interest in many models of acquired and inherited skeletal muscle pathology. The present study focuses on the sialylation changes in mouse skeletal muscle after invasion by the parasitic nematode Trichinella spiralis (Owen, 1835). Asynchronous infection with T. spiralis was induced in mice that were sacrificed at different time points of the muscle phase of the disease. The amounts of free sialic acid, sialylated glycoproteins and total sialyltransferase activity were quantified. Histochemistry with lectins specific for sialic acid was performed in order to localise distribution of sialylated glycoconjugates and to clarify the type of linkage of the sialic acid residues on the carbohydrate chains. Elevated intracellular accumulation of α-2,3-and α-2,6-sialylated glycoconjugates was found only within the affected sarcoplasm of muscle fibres invaded by the parasite. The levels of free and protein-bound sialic acid were increased and the total sialyltransferase activity was also elevated in the skeletal muscle tissue of animals with trichinellosis. We suggest that the biological significance of this phenomenon might be associated with securing integrity of the newly formed nurse cell within the surrounding healthy skeletal muscle tissue. The increased sialylation might inhibit the affected muscle cell contractility through decreased membrane ion gating, helping the parasite accommodation process.
"In addition, aberrant glycosylation and disruption of the O-mannose glycan of αDG, due to mutations in glycan processing genes, leads to the development of muscular dystrophies known as secondary dystroglycanopathies . Dystroglycanopathies cause a range of mild to severe pathologies and include diseases such as Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, and muscle-eye-brain disease , , . To date, αDG O-mannose glycosylation disorders have been linked to mutations in more than a dozen genes, including FKTN (fukutin), establishing a prevalent family of autosomal recessive muscular dystrophies . "
[Show abstract][Hide abstract] ABSTRACT: Alpha-dystroglycan requires a rare O-mannose glycan modification to form its binding epitope for extracellular matrix proteins such as laminin. This functional glycan is disrupted in a cohort of muscular dystrophies, the secondary dystroglycanopathies, and is abnormal in some metastatic cancers. The most commonly used reagent for detection of alpha-dystroglycan is mouse monoclonal antibody IIH6, but it requires the functional O-mannose structure for recognition. Therefore, the ability to detect alpha-dystroglycan protein in disease states where it lacks the full O-mannose glycan has been limited. To overcome this hurdle, rabbit monoclonal antibodies against the alpha-dystroglycan C-terminus were generated. The new antibodies, named 5-2, 29-5, and 45-3, detect alpha-dystroglycan from mouse, rat and pig skeletal muscle by Western blot and immunofluorescence. In a mouse model of fukutin-deficient dystroglycanopathy, all antibodies detected low molecular weight alpha-dystroglycan in disease samples demonstrating a loss of functional glycosylation. Alternately, in a porcine model of Becker muscular dystrophy, relative abundance of alpha-dystroglycan was decreased, consistent with a reduction in expression of the dystrophin-glycoprotein complex in affected muscle. Therefore, these new rabbit monoclonal antibodies are suitable reagents for alpha-dystroglycan core protein detection and will enhance dystroglycan-related studies.
PLoS ONE 05/2014; 9(5):e97567. DOI:10.1371/journal.pone.0097567 · 3.23 Impact Factor
"Only one case has been reported so far with a pathogenic mutation in the dystroglycan (DAG1) gene itself , which therefore represents a primary dystroglycanopathy; the other eight genes encode proteins with confirmed or putative roles in the glycosylation of α-dystroglycan and are therefore secondary dystroglycanopathies. Among these are the glycosyltransferases that transfer glycan structures onto α-dystroglycan: protein O-mannosyltransferases 1 and 2 (POMT1 and 2) ; protein O-linked-mannose β-1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) , and Large ; and the putative glycosyltransferases fukutin  and fukutin-related protein . Two recently identified genes that encode for dolichol-phosphate-mannose synthase (DPM) subunits DPM2  and DPM3  have also been found to be defective in patients with a dystroglycanopathy phenotype, consistent with the role of the DPM complex in the synthesis of glycan precursors for the O-mannosyl glycosylation of α-dystroglycan. "
[Show abstract][Hide abstract] ABSTRACT: The dystrophin-associated glycoprotein complex (DGC) is found at the muscle fiber sarcolemma and forms an essential structural link between the basal lamina and internal cytoskeleton. In a set of muscular dystrophies known as the dystroglycanopathies, hypoglycosylation of the DGC component α-dystroglycan results in reduced binding to basal lamina components, a loss in structural stability, and repeated cycles of muscle fiber degeneration and regeneration. The satellite cells are the key stem cells responsible for muscle repair and reside between the basal lamina and sarcolemma. In this study, we aimed to determine whether pathological changes associated with the dystroglycanopathies affect satellite cell function. In the Large(myd) mouse dystroglycanopathy model, satellite cells are present in significantly greater numbers but display reduced proliferation on their native muscle fibers in vitro, compared with wild type. However, when removed from their fiber, proliferation in culture is restored to that of wild type. Immunohistochemical analysis of Large(myd) muscle reveals alterations to the basal lamina and interstitium, including marked disorganization of laminin, upregulation of fibronectin and collagens. Proliferation and differentiation of wild-type satellite cells is impaired when cultured on substrates such as collagen and fibronectin, compared with laminins. When engrafted into irradiated tibialis anterior muscles of mdx-nude mice, wild-type satellite cells expanded on laminin contribute significantly more to muscle regeneration than those expanded on fibronectin. These results suggest that defects in α-dystroglycan glycosylation are associated with an alteration in the satellite cell niche, and that regenerative potential in the dystroglycanopathies may be perturbed. STEM Cells2012;30:2330-2341.
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