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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormalities of dystrophin, the sarcoglycans, and laminin alpha2 are responsible for a subset of the muscular dystrophies. In this study we aim to characterise the nature and frequency of abnormalities of these proteins in an Australian population and to formulate an investigative algorithm to aid in approaching the diagnosis of the muscular dystrophies. To reduce ascertainment bias, biopsies with dystrophic (n=131) and non-dystrophic myopathic (n=71) changes were studied with antibodies to dystrophin, alpha, beta, and gamma sarcoglycan, beta dystroglycan, and laminin alpha2, and results were correlated with clinical phenotype. Abnormalities of dystrophin, the sarcoglycans, or laminin alpha2 were present in 61/131 (47%) dystrophic biopsies and in 0/71 myopathic biopsies, suggesting that immunocytochemical study of dystrophin, the sarcoglycans, and laminin alpha2 may, in general, be restricted to patients with dystrophic biopsies. Two patients with mutations identified in gamma sarcoglycan had abnormal dystrophin (by immunocytochemistry and immunoblot), showing that abnormalities of dystrophin may be a secondary phenomenon. Therefore, biopsies should not be excluded from sarcoglycan analysis on the basis of abnormal dystrophin alone. The diagnostic yield was highest in those with severe, rapidly progressive limb-girdle weakness (92%). Laminin alpha2 deficiency was identified in 5/131 (4%) patients; 215 patients presented after infancy, indicating that abnormalities of laminin alpha2 are not limited to the congenital muscular dystrophy phenotype. Overall patterns of immunocytochemistry and immunoblotting provided a guide to mutation analysis and, on the basis of this study, we have formulated a diagnostic algorithm to guide the investigation of patients with muscular dystrophy.
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PMID:Abnormalities of dystrophin, the sarcoglycans, and laminin alpha2 in the muscular dystrophies. 961 Aug

We report clinical, biopsy and autopsy findings in a merosin-deficient congenital muscular dystrophy (CMD) infant with abnormal cortical gyration. Brain showed polymicrogyria and occipital agyria with marginal neuroglial heterotopia and inferior vermis hypoplasia. There was a normal pattern of myelination consistent with early age. Laminin alpha 2 chain was also absent in myocardium, brain pial-glial membrane, brain and skin blood vessels as well as intramuscular and skin nerves. Occasional basal lamina gaps were found in muscle fibres but not in brain-blood vessels. This is the first autopsy study in a merosin-deficient CMD case with abnormal cortical gyration.
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PMID:Merosin-deficient congenital muscular dystrophy associated with abnormal cerebral cortical gyration: an autopsy study. 1022 Aug 63

Laminin alpha2 chain-deficient congenital muscular dystrophy (CMD) is diagnosed by genetic analysis and by immunohistochemistry. Since laminin alpha2 chain is expressed in placental trophoblasts, the demonstration of its deficiency in chorionic villi is a useful aid to prenatal diagnosis. We present our experience with the use of the immunohistochemical method for prenatal diagnosis in four women, all of whom had at least one child with laminin alpha2 chain-deficient CMD. Immunohistochemistry provided a rapid procedure for prenatal diagnosis, and follow-up of these four cases confirmed its reliability.
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PMID:Laminin alpha2 deficient congenital muscular dystrophy: prenatal diagnosis. 1036 79

dy/dy mice, which carry an unidentified mutation in the Lama2 gene, show dystrophic pathologies similar to those of human congenital muscular dystrophy. Laminin alpha2 deficiency induces apoptosis with DNA fragmentation. Caspases, which are involved in various types of cell death, are sequentially activated through a processing by other members of caspases. By using a cleavage site-directed antibody against caspase-3 that specifically reacts with the active form of caspase-3, we immunochemically demonstrated that caspase-3 is activated in the skeletal muscle fiber of dy/dy mice and that some of the activated caspase-3 muscle fibers are TUNEL-positive. Thus the lack of laminin alpha2 signals activates caspase-3, resulting in the apoptosis of muscle fibers.
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PMID:Activation of caspase-3 apoptotic pathways in skeletal muscle fibers in laminin alpha2-deficient mice. 1038 57

Laminins are a family of glycoproteins which are ubiquitous components of basement membranes and play key structural and functional roles. Eleven isoforms have been identified to date; each is an alpha beta gamma heterotrimer assembled from a repertoire of five alpha, three beta and two gamma chains. Studies of laminin-11 (alpha 5 beta 2 gamma 1) illustrate the unique expression patterns and distinct functions that can be displayed by laminin isoforms. Laminin-11 is found in the glomerular basement membrane in kidney, in the neuromuscular synaptic cleft in skeletal muscle and in other tissues such as placenta and lung. Mice lacking laminin-11 exhibit defective glomerular filtration and developmental defects in neuromuscular synapse formation, with Schwann cells invading the synaptic cleft. Consistent with these observations, both motoneurons and Schwann cells distinguish laminin-11 from other isoforms in vitro. These results suggest that laminin-11 is a structural component of the basement membrane which influences cell behavior in physiologically relevant ways. A greater understanding of laminin-11 assembly and basement membrane incorporation could provide a logical basis for therapy in merosin-deficient congenital muscular dystrophy.
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PMID:Laminin-11. 1048 Dec 68

Laminin-2 is part of the basement membrane of the skeletal muscle fibers. The laminin alpha 2 chain is absent or drastically reduced in a subgroup of congenital muscular dystrophy patients, and in the severely affected dystrophic dy/dy mouse. We previously reported that heterogeneous primary mouse muscle cell cultures conferred laminin alpha 2 chain expression in dy/dy mice muscles upon cell transplantation. In the present study we investigated whether pure myoblast cell lines were able to confer laminin alpha 2 chain expression in vivo. We observed that: (1) xeno-transplantation of non-immortalized human myoblast in SCID mouse muscles allows human laminin alpha 2 chain expression; (2) allotransplantation of the permanent G8 mouse myoblast cell line in dy/dy muscles allows the expression of the murine laminin alpha 2 chain; and (3) allo-transplantation of the D7 dystrophic dy/dy cell line allows the formation of new and hybrid muscle fibers in dy/dy muscle in the absence of laminin alpha 2 chain expression. We conclude that normal myoblasts are able to restore the expression of an extracellular skeletal muscle protein and that the absence of laminin-2 does not prevent transplanted muscle cells from participating in the formation of myofibers. Myoblasts are, therefore, attractive tools for further exploration of gene complementation strategies in the animal models of congenital muscular dystrophy.
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PMID:Myoblast transplantations lead to the expression of the laminin alpha 2 chain in normal and dystrophic (dy/dy) mouse muscles. 1050 3

Merosin (also called as Laminin-2) is an isoform of laminin comprised of the alpha2, beta1 and gamma1 chains. In European populations, half of the patients with classical congenital muscular dystrophy have mutations of the LAMA2 gene (6q22-23) and present reduced or absence of laminin alpha2 chain. This form is generally referred to as merosin-deficient CMD. Merosin-deficient CMD is characterized by involvement of not only skeletal muscle but also central and peripheral nervous systems: Extensive brain white matter abnormalities are found by magnetic resonance imaging (MRI). However, most patients show no mental retardation. Recent case studies reported that some patients have several structural abnormalities such as abnormal cerebral cortical gyration, hypoplasia of cerebellum and pons, and dilation of ventricles. At present, functions of merosin related to muscle degeneration have not been fully elucidated. In addition, the mechanisms responsible for pathogenesis of diffuse brain white matter abnormalities remain to be determined. As mouse models for merosin-deficient CMD, three spontaneous mutants(dy, dy(2J), dy(PAS1)) and two mutants named dy(W) and dy(3K) by targeted gene disruption have been reported. These mice will help to elucidate the pathogenesis of merosin-deficient CMD and serve to develop therapy.
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PMID:Merosin and congenital muscular dystrophy. 1067 65

The laminin alpha2 chain is a major component of basal lamina in both skeletal muscle and the peripheral nervous system. Laminin alpha2 chain deficiency causes merosin-deficient congenital muscular dystrophy, which affects not only skeletal muscles, but also the peripheral and central nervous systems. It has been reported that the formation of basal lamina is required for myelination in the peripheral nervous system. In fact, the spinal root of dystrophic mice (dy/dy mice), whose laminin alpha2 chain expression is greatly reduced, shows lack of basal lamina and clusters of naked axons. To investigate the role of laminin alpha2 chain and basal lamina in vivo, we examined the peripheral nervous system of dy3K/dy3K mice, which are null mutants of laminin alpha2 chain. The results indicate the presence of myelination although Schwann cells lacked basal lamina in the spinal roots of dy3K/dy3K mice, suggesting that basal lamina is not an absolute requirement for myelination in vivo. Immunohistochemically, the expression of laminin alpha4 chain was increased and laminin alpha5 chain was preserved in the endoneurium of the spinal root. Laminin alpha4 and alpha5 chains may play the critical role in myelination instead of laminin alpha2 chain in dy3K/dy3K mice. In addition, the motor conduction velocity of the sciatic nerve was significantly reduced compared with that of wild-type littermate. This reduction in conduction velocity may be due to small axon diameter, thin myelin sheath and the patchy disruption of the basal lamina of the nodes of Ranvier in dy3K/dy3K mice.
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PMID:Schwann cell myelination occurred without basal lamina formation in laminin alpha2 chain-null mutant (dy3K/dy3K) mice. 1146 Feb 66

Laminin alpha2 (merosin)-deficient congenital muscular dystrophy (CMD) patients show progressive muscle fiber necrosis and ineffective muscle regeneration, probably due to a lower formation of multinucleated myotubes due to an adhesion defect of myoblasts to each other. Some recent studies found that CMD patients have a white matter disorder and cerebellum atrophy. In the spinal cord of dy mice, a model of CMD, inducible nitric oxide synthase (iNOS) was markedly expressed. Using Western blotting and immunohistochemical analyses, we investigated the levels of neurotrophin-4 (NT-4), brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) in the central nervous system and skeletal muscles of dy mice. In the dy mice, the microtubule-associated protein-2 (MAP-2) protein level was markedly decreased in the Purkinje and granule cells of the cerebellum, and in lumbar motoneurons of the spinal cord. The motoneurons and axons of dy mice possessed lower expressions of phosphorylated tau. The amount of NT-4 was markedly lower in the cerebellum, spinal cord and hindlimb muscles of dy mice. In dy mice, GDNF was markedly enhanced in the Purkinje and granule cells of the cerebellum, in many lumbar motoneurons, and in the regenerating atrophied fibers. The CNTF protein level did not differ in the hindlimb muscles between the normal and dy mice. Therefore, GDNF could act to inhibit the death of Purkinje and granular neurons, and motoneurons, and to promote the remodeling of the neuromuscular junction of atrophied muscle fibers of dy mice. Furthermore, dy mice include neurogenic abnormalities in the cerebellum and spinal cord along with myogenic disorder of muscle fibers.
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PMID:The reciprocal change of neurotrophin-4 and glial cell line-derived neurotrophic factor protein in the muscles, spinal cord and cerebellum of the dy mouse. 1241 Mar 96

The transmembrane protein Dystroglycan is a central element of the dystrophin-associated glycoprotein complex, which is involved in the pathogenesis of many forms of muscular dystrophy. Dystroglycan is a receptor for multiple extracellular matrix (ECM) molecules such as Laminin, agrin and perlecan, and plays a role in linking the ECM to the actin cytoskeleton; however, how these interactions are regulated and their basic cellular functions are poorly understood. Using mosaic analysis and RNAi in the model organism Drosophila melanogaster, we show that Dystroglycan is required cell-autonomously for cellular polarity in two different cell types, the epithelial cells (apicobasal polarity) and the oocyte (anteroposterior polarity). Loss of Dystroglycan function in follicle and disc epithelia results in expansion of apical markers to the basal side of cells and overexpression results in a reduced apical localization of these same markers. In Dystroglycan germline clones early oocyte polarity markers fail to be localized to the posterior, and oocyte cortical F-actin organization is abnormal. Dystroglycan is also required non-cell-autonomously to organize the planar polarity of basal actin in follicle cells, possibly by organizing the Laminin ECM. These data suggest that the primary function of Dystroglycan in oogenesis is to organize cellular polarity; and this study sets the stage for analyzing the Dystroglycan complex by using the power of Drosophila molecular genetics.
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PMID:Dystroglycan is required for polarizing the epithelial cells and the oocyte in Drosophila. 1244 1


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