Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Laminin-2 (merosin) is a heterotrimer composed of alpha 2, beta 1 and gamma 1 chains. Approximately half of the cases with the classical form of congenital muscular dystrophy (CMD) have a deficiency of the laminin alpha 2 chain, encoded by the LAMA2 gene on chromosome 6q22. This disorder is often termed merosin-deficient CMD. Skeletal and cardiac muscle, and the peripheral and central nervous systems, all express laminin alpha 2 and can be affected in merosin-deficient CMD. Normal skin also expresses all three chains of laminin-2 at the epidermal/dermal junction, around hair follicles and in the sensory nerves. Skin biopsies can therefore be used to assess merosin status in patients. We show here an absence of laminin alpha 2 in skin from four cases of CMD with a severe phenotype and abnormal magnetic resonance image (MRI) of the brain, in contrast to normal expression in one case of mild CMD with normal MRI, and in five controls. An additional case of CMD had a partial deficiency of laminin alpha 2 in the skin and severe motor disability, but a normal MRI. Sensory nerves in this case showed normal expression of laminin alpha 2, in contrast to its absence in the severe cases. The expression of laminin beta 1 was also reduced in skin from cases of merosin-deficient CMD. In contrast to human fetal muscle, the laminin alpha 2 protein was not detected in fetal skin up to 23 weeks of gestation. The laminin beta 1 and gamma 1 chains, and the mRNA for laminin alpha 2, however, were present. Studies of mRNA of cultured skin cells suggest that fibroblasts are the major source of laminin alpha 2, not keratinocytes. Our data show that skin is useful for the assessment of merosin status in patients with CMD and that skin fibroblasts may be a useful source of tissue-specific RNA. In addition, we show that there is a tissue-specific difference in the developmental expression of the laminin alpha 2 protein.
 ...
PMID:Expression of laminin chains in skin in merosin-deficient congenital muscular dystrophy. 930 12

Integrin alpha 7 beta 1 is a specific cellular receptor for the basement membrane protein laminin-1 (refs 1,2), as well as for the laminin isoforms -2 and -4 (ref. 3). The alpha 7 subunit is expressed mainly in skeletal and cardiac muscle and has been suggested to be involved in differentiation and migration processes during myogenesis. Three cytoplasmic and two extracellular splice variants that have been described are developmentally regulated and expressed in different sites in the muscle. In adult muscle, the alpha 7A and alpha 7B subunits are concentrated in myotendinous junctions but can also be detected in neuromuscular junctions and along the sarcolemmal membrane. To study the potential involvement of alpha 7 integrin, during myogenesis and its role in muscle integrity and function, we generated a null allele of the alpha 7 gene (Itga7) in the germline of mice by homologous recombination in embryonic stem (ES) cells. Surprisingly, mice homozygous for the mutation are viable and fertile, indicating that the alpha 7 beta 1 integrin is not essential for myogenesis. However, histological analysis of skeletal muscle revealed typical symptoms of a progressive muscular dystrophy starting soon after birth, but with a distinct variability in different muscle types. The observed histopathological changes strongly indicate an impairment of function of the myotendinous junctions. These findings demonstrate that alpha 7 beta 1 integrin represents an indispensable linkage between the muscle fibre and the extracellular matrix that is independent of the dystrophin-dystroglycan complex-mediated interaction of the cytoskeleton with the muscle basement membrane.
 ...
PMID:Absence of integrin alpha 7 causes a novel form of muscular dystrophy. 935 97

The beta 1 integrin subunit is identical with the CD29 antigen, which is found at the surface of leukocytes. Integrins are involved in cell-cell and cell-matrix adhesion, mediate neuronal attachment and neurite outgrowth in response to extracellular matrix proteins in cell culture systems. A few analyses of beta 1 integrin subunit have been done on developing and regenerating skeletal muscle in animals; but cell culture systems and animal models differ in some respects from human skeletal muscle in situ. The expression of a beta 1 integrin subunit variant in human skeletal muscle was reported merely by Western blot analysis. Our present study, performed with immunohistochemical procedures, attempts to demonstrate the expression of the beta 1 integrin subunit in developing, normal adult, and diseased human skeletal muscles. The results demonstrated that the beta 1 integrin subunit is expressed in developing, normal adult, regenerating, and denervated human skeletal muscle. In developing muscle, the beta 1 integrin subunit was observed in muscle cells at least from 12 to 16 weeks of gestation. In muscular dystrophy and inflammatory myopathy the beta 1 integrin subunit staining occurs in basophilic muscle fibers. Furthermore, the beta 1 integrin subunit is expressed in mature fast twitch type 2 fibers, and in denervated myocytes in neurogenic muscular atrophy. On serial sections, the beta 1 integrin subunit, N-CAM (neural cell adhesion molecule) and vimentin are expressed in identical muscle fibers. However, in mature fast twitch type 2 fibers the beta 1 integrin subunit is expressed exclusively and in neurogenic muscular atrophy vimentin expression is weak. In conclusion, the beta 1 integrin subunit, in human skeletal muscles, probably plays a role in the growth morphology and innervation of developing, regenerating, and denervated myocytes. Furthermore, the observation that the beta 1 integrin subunit is enriched in mature fast twitch type 2 fibers indicates that the beta 1 integrin subunits may play a role in transducing mechanical forces to extracellular matrix proteins.
 ...
PMID:Light-microscopic study of the beta 1 integrin subunit in human skeletal muscle. 940 99

Normal peripheral nerve myelination depends on Schwann cell-basal lamina interactions. An important component of Schwann cell basal lamina is laminin--predominantly laminins 2 and 4. Mutations in the alpha 2 chain common to these two isoforms are associated with dysmyelination in mouse (dy) and man (congenital muscular dystrophy). Thus, laminin 2 and 4 receptors are also likely to be important for myelin formation. Several laminin 2/4 receptors are detected at the basal lamina surface of myelin-forming Schwann cells, namely, alpha 6 beta 4 and alpha 6 beta 1 integrins and dystroglycan. The evidence linking these receptors to myelination is suggestive, but not conclusive. Genetic studies have not yet confirmed a role for these molecules in myelin formation. Natural or targeted inactivation of alpha 6, beta 4, and beta 1 integrins and of dystroglycan have profound effects on other tissues causing embryonic or perinatal death before myelination. Therefore, to conditionally inactivate these receptors specifically in myelin-forming Schwann cells, we have constructed and initially characterized a P0-Cre transgene that activates Cre-mediated recombination of loxP-containing genes in peripheral nerve.
 ...
PMID:P0-Cre transgenic mice for inactivation of adhesion molecules in Schwann cells. 1058 37

Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the alpha 7 beta 1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), alpha 2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and alpha 7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the alpha 7 beta 1 integrin can compensate for the absence of dystrophin, we expressed the rat alpha 7 chain in mdx/utr(-/-) mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely. Using the muscle creatine kinase promoter, expression of the alpha 7BX2 integrin chain was increased 2.0-2.3-fold in mdx/utr(-/-) mice. Concomitant with the increase in the alpha 7 chain, its heterodimeric partner, beta 1D, was also increased in the transgenic animals. Transgenic expression of the alpha 7BX2 chain in the mdx/utr(-/-) mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering alpha 7 beta 1 integrin-mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr(-/-) mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the alpha 7 beta 1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis, gait, joint contractures, and mobility in mdx/utr(-/-) and alpha 7BX2-mdx/utr(-/-) mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.
 ...
PMID:Enhanced expression of the alpha 7 beta 1 integrin reduces muscular dystrophy and restores viability in dystrophic mice. 1125 21

In dystrophic mice, a model of merosin-deficient congenital muscular dystrophy, laminin-2 mutations produce peripheral nerve dysmyelination and render Schwann cells unable to sort bundles of axons. The laminin receptor and the mechanism through which dysmyelination and impaired sorting occur are unknown. We describe mice in which Schwann cell-specific disruption of beta1 integrin, a component of laminin receptors, causes a severe neuropathy with impaired radial sorting of axons. beta 1-null Schwann cells populate nerves, proliferate, and survive normally, but do not extend or maintain normal processes around axons. Interestingly, some Schwann cells surpass this problem to form normal myelin, possibly due to the presence of other laminin receptors such as dystroglycan and alpha 6 beta 4 integrin. These data suggest that beta 1 integrin links laminin in the basal lamina to the cytoskeleton in order for Schwann cells to ensheath axons, and alteration of this linkage contributes to the peripheral neuropathy of congenital muscular dystrophy.
 ...
PMID:Conditional disruption of beta 1 integrin in Schwann cells impedes interactions with axons. 1178 30

Most proteins within living organisms contain glycans. Glycan structures can modulate the biological properties and function of glycoproteins. Developments in glycobiology have revealed a new type of glycosidic linkage to the peptide portion, the O-mannosyl linkage in mammals, although heretofore it had been thought to be specific to yeast. One of the best known O-mannosyl-modified glycoproteins is dystroglycan, which is a central component of dystrophinglycoprotein complex isolated from skeletal muscle membranes. We identify and characterize a glycosyltransferase, UDP-N-acetylglucosamine: protein O-mannose beta 1,2-N-acetylglucosaminyltransferase (POMGnT1), involved in the biosynthesis of mammalian type O-mannosyl glycans. Finally, we find that the POMGnT1 gene is responsible for muscle-eye-brain disease (MEB). MEB is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities and brain malformation (type II lissencephaly). Like MEB, recent data suggest that the aberrant protein glycosylation of a specific glycoprotein, alpha-dystroglycan, is the primary cause of some forms of congenital muscular dystrophy. Here I review the new insight into glycobiology of muscular dystrophy and neuronal migration disorder.
 ...
PMID:[Finding of O-mannosyl glycan in mammals and congenital muscular dystrophies due to glycosylation defects]. 1457 28

Various autoantibodies had been detected in patients with dilated cardiomyopathy (DCM). Among them, anti-beta 1 adrenoreceptor antibody (ARAb) had been proven to act as agonist on beta 1 adrenoreceptor and cause DCM. Cardiomyopathy is also serious problem in progressive muscular dystrophy (PMD). Because cardiac dysfunction is quite variable even in siblings sharing identical mutations, it is highly possible that there are some modifier factors. Thus, we measured ARAb in 93 patients with PMD and 11 patients with DCM to clarify immune function for cardiac impairment of PMD. The titer was abnormally elevated in 30.1% of PMD, 72.7% of DCM and 75.0% (9/12) of PMD patients with symptomatic cardiac failure. ARAb was weakly correlated to fractional shortening, brain natriuretic peptide, noradrenalin and severity of premature ventricular contractions (Lown grade). During the study period, four patients developed cardiac failure and ARAb was increased in all these patients. In DMD, although the patients receiving both beta blocker and angiotensin converting enzyme inhibitor showed worst cardiac function, the titers were rather low compared to patients with angiotensin converting enzyme inhibitor alone. Four of five patients initiating beta blocker showed decrease of ARAb. Autoantibodies for myocardium actually exist in PMD in certain ratio as is the case with DCM. It is highly possible that immune system plays some role in cardiac impairment even in PMD. We should pay enough attention to immune system to elucidate the mechanism of cardiac dysfunction and refine strategy of cardiac treatments.
 ...
PMID:[Anti-beta 1 adrenoreceptor antibody is frequently elevated in patients with muscular dystrophy]. 1732 76


<< Previous 1 2