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

Dystrophin is a large cytoskeletal protein encoded by the Duchenne muscular dystrophy (DMD) gene. Dystrophin is associated with a large oligomeric complex of sarcolemmal glycoproteins, including the novel laminin-binding glycoprotein called dystroglycan, which provides a linkage to the extracellular matrix. In DMD, the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins. In severe childhood autosomal recessive muscular dystrophy with DMD-like phenotype (SCARMD), a specific deficiency of the 50 kDa dystrophin-associated glycoprotein is found. Thus, the disruption/dysfunction of the dystrophin-glycoprotein complex due to the deficiency of one or more of the dystrophin-associated proteins is presumed to cause the disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix. This may render muscle cells susceptible to necrosis in two forms of severe childhood muscular dystrophy, DMD and SCARMD.
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PMID:Deficiency of dystrophin-associated proteins: a common mechanism leading to muscle cell necrosis in severe childhood muscular dystrophies. 835 36

Dystoroglycan is encoded by a single gene and cleaved into two proteins, alpha and beta-dystroglycan, by posttranslational processing. The 120kDa peripheral nerve isoform of alpha-dystroglycan binds laminin-2 comprised of the alpha 2, beta 1, and gamma 1 chains. In congenital muscular dystrophy and dy mice deficient in laminin alpha 2 chain, peripheral myelination is disturbed, suggesting a role for the dystroglycan- laminin interaction in peripheral myelinogenesis. To begin to test this hypothesis, we have characterized the dystroglycan-laminin interaction in peripheral nerve. We demonstrate that (1) alpha-dystroglycan is an extracellular peripheral membrane glycoprotein that links beta-dystroglycan in the Schwann cell outer membrane with laminin-2 in the endoneurial basal lamina, and (2) dystrophin homologues Dp116 and utrophin are cytoskeletal proteins of the Schwann cell cytoplasm. We also present data that suggest a role for glycosylation of alpha-dystroglycan in the interaction with laminin.
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PMID:Characterization of dp6troglycan-laminin interaction in peripheral nerve. 862 7

Recently, a deficiency of merosin has been reported in patients with classical congenital muscular dystrophy (CMD), while other patients, with indistinguishable clinico-pathological features, do not present this deficiency, suggesting genetic heterogeneity. The purpose of the present investigation was to assess merosin distribution and quantity in 21 clinically well characterized Brazilian CMD patients, in order to: a) estimate the proportion of merosin-deficient cases in this group of patients; b) characterize phenotypically merosin-negative, as compared to merosin-positive patients. Merosin deficiency was found in 11 patients and all the seven who had been submitted to neuroimaging studies showed evidence of periventricular dysmyelination. A normal pattern of 43 DAG was found in all patients, which suggest that this protein is not preferentially involved in a third form of merosin-positive CMD. Results from the present study are further suggestive, but do not prove, that the association of merosin deficiency with white matter alterations represents a genetic entity with common clinical, laboratory and neuroimaging findings.
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PMID:Deficiency of merosin (laminin M or alpha 2) in congenital muscular dystrophy associated with cerebral white matter alterations. 871 43

Dystrophin is associated with several novel sarcolemmal proteins via the cysteine-rich/C-terminal domains. The dystrophin-associated proteins are classified into three groups: (1) alpha- and beta-dystroglycan, (2) adhalin, 35DAG and A3b, and (3) members of the syntrophin family. Dystrophin interacts with F-actin via the N-terminal domain. Alpha-dystroglycan binds laminin-2, a major component of the basal lamina. These findings indicate that the dystrophin-glycoprotein complex (DGC) links the subsarcolemmal cytoskeleton with the basal lamina, thus providing mechanical stability to the sarcolemmal. The DGC may also play a role in signal transduction. We have reported previously the deficiency of adhalin in skeletal muscle of Arab patients afflicted with severe childhood autosomal recessive muscular dystrophy (SCARMD). SCARMD is now known to affect other races including Europeans and Japanese. Although the phenotype of this disease can mimic Duchenne muscular dystrophy in severe cases, it is sometimes quite mild. SCARMD is genetically heterogeneous. Recently, adhalin gene mutations have been demonstrated in European, Arab and Japanese families with SCARMD. Another locus is on chromosome 13q, however, the mutated gene remains elusive. In the advanced stages of SCARMD, the expression of laminin is disturbed, suggesting that adhalin deficiency may cause the dysfunction of the DGC as a laminin receptor, which may eventually lead to muscle cell death.
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PMID:[Severe childhood autosomal recessive muscular dystrophy]. 875 17

The WW domain is a structured protein module found in a wide range of regulatory, cytoskeletal, and signaling molecules. Its ligands contain proline-rich sequences, some of which show a core consensus of XPPXY that is critical for binding. In order to gain a better understanding of the molecular and biological functions of WW domains, we decided to predict their cognate ligands by searching databases for proteins containing the XPPXY consensus. Using several axioms that take into account evolutionary conservation and functional similarity, we have identified four groups of proteins representing candidate ligands that signal through known or unknown WW domains. These include viral Gag proteins, sodium channels, interleukin receptors, and a subgroup of serine/threonine kinases. In addition, we proposed that dystrophin and beta-dystroglycan bind through the WW-XPPXY link and that interference with this interaction could result in muscular dystrophy. Our study provides guidelines for experiments to probe the molecular and biological functions of the WW domain-ligand connection. Should these predictions be proven empirically, the results may have important ramifications for basic research and medicine.
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PMID:Towards prediction of cognate complexes between the WW domain and proline-rich ligands. 879 92

"Classic" congenital muscular dystrophy is a heterogeneous group of disorders, characterized by early-onset muscle weakness and hypotonia, absence of overt cerebral or ocular symptoms, and muscle pathology consistent with a dystrophic process. A subset of patients with congenital muscular dystrophy have recently been found to be deficient in the extracellular matrix protein merosin. Consequently, we reviewed the clinical, pathologic, and immunohistochemical features of 12 patients (six males and six females) with classic congenital muscular dystrophy who have been seen at the Children's Hospital, Boston, over the past 15 years. There was marked clinical heterogeneity within this patient population, with age of independent ambulation ranging from 13 months to 6 years. Immunocytochemical analysis using antibodies to merosin, dystrophin, 43-kDa dystroglycan, adhalin, and laminin was normal in 11 of 12 patients. One patient had markedly abnormal staining for merosin; the majority of fibers were negative, although occasional fibers demonstrated patchy staining. Immunoblot analysis in this patient demonstrated markedly reduced levels of merosin (< 10% compared to controls and other patient), of apparently normal size. Clinically, this patient could be differentiated from the others by a marked elevation of serum creatine kinase (> 1000 U/L) and the presence of early white-matter changes on magnetic resonance imaging. The results of this study support the observation that abnormalities of merosin are present in a subgroup of patients with classic congenital muscular dystrophy. Although marked elevation of serum creatine kinase and white-matter changes on magnetic resonance imaging may serve to distinguish these patients from other patients with congenital muscular dystrophy, there remains a large proportion of patients in whom the underlying pathogenesis remains to be elucidated.
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PMID:Congenital muscular dystrophy associated with merosin deficiency. 880 18

Dystroglycan provides a crucial linkage between the cytoskeleton and the basement membrane for skeletal muscle cells. Disruption of this linkage leads to various forms of muscular dystrophy. Significant recent advances in understanding the structure and function of dystroglycan include detailed in vitro and in vivo analyses of its binding partners in muscle, an examination of its function at the neuromuscular junction, and emerging evidence of its roles in nonmuscle tissues.
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PMID:Dystroglycan: an extracellular matrix receptor linked to the cytoskeleton. 893 60

beta-Dystroglycan, a 43-kd transmembrane dystrophin-associated glycoprotein, plays an important role in linking dystrophin to the laminin-binding alpha-dystroglycan. alpha-/beta-Dystroglycan is encoded by a single gene on chromosome 3p21 and ubiquitously expressed in muscle and nonmuscle tissues. No known human diseases have been mapped to this locus. Here, we describe the selective deficiency of beta-dystroglycan in a 4-year-old Saudi boy with muscular dystrophy. The patient had a borderline elevation of serum creatine kinase level and early-onset proximal symmetrical muscle weakness and wasting without calf hypertrophy. The milder phenotype may suggest a secondary deficiency of beta-dystroglycan; however, the unique immunofluorescence labeling suggests that the patient may present a novel form of muscular dystrophy.
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PMID:Muscular dystrophy associated with beta-Dystroglycan deficiency. 900

Merosin, also called laminin-2, is an isoform of laminin comprised of the alpha 2, beta 1 and gamma 1 chains. Deficiency of merosin alpha 2 chain was recently identified as the primary cause of the classical form of congenital muscular dystrophy (CMD), an autosomal recessive neuromuscular disorder characterised by muscular dystrophy and brain white matter abnormalities. Interestingly, merosin-deficient CMD and its animal model dy mouse are also accompanied by dysmyelination of peripheral motor nerves. In peripheral nerve, merosin is expressed in the endoneurium surrounding the Schwann cell/myelin sheath, while the putative merosin receptors dystroglycan and alpha 6 beta 4 integrin are expressed in the outer membrane of Schwann cell/myelin sheath. Together with the well known fact that the deposition of laminin in the basement membrane is essential for Schwann cell myelination, these findings indicate that the interaction of merosin with dystroglycan and/or alpha 6 beta 4 integrin plays an important role in peripheral myelinogenesis and that the disturbance of this interaction leads to peripheral dysmyelination in merosin deficiency. The clinical significance of peripheral dysmyelination in merosin deficiency is also discussed.
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PMID:Peripheral nerve involvement in merosin-deficient congenital muscular dystrophy and dy mouse. 913 44

A girl born from consanguineous Turkish parents had marked hypotonia from birth and delayed milestones. She was able to stand unaided by 3 years of age with then progressive worsening of motor abilities. She had a severe non-progressive mental deficiency. Epilepsy occurred by 6 years of age. Ophthalmological investigation was normal. A marked white matter high signal was seen on magnetic resonance imaging without cortical dysplasia. Dystrophic changes were seen on muscle biopsy. Two brothers had had a similar history with early death. Muscular immunocytochemical studies showed a normal staining for dystrophin and all dystrophin related glycoproteins (including 43 and 50 DAG). Merosin staining was normal. This case differs from Fukuyama's congenital dystrophy, from merosin negative congenital muscular dystrophy, or from other congenital muscular dystrophy with CNS dysfunction. It underlines the heterogeneity of congenital muscular dystrophy and the non-specific aspect of white matter changes on neuro-imaging.
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PMID:Merosin positive congenital muscular dystrophy with mental deficiency, epilepsy and MRI changes in the cerebral white matter. 918 83


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