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)

Primary deficiency of merosin is the cause of the classic form of congenital muscular dystrophy (CMD) accompanied by brain white matter abnormalities. We report a female infant with dystrophinopathy who was deficient in merosin in skeletal muscle. The patient had a phenotype of typical CMD and white matter abnormalities on brain MRI. Merosin was greatly reduced in the biopsied skeletal muscle. However, the expression of dystroglycan and syntrophin was also greatly reduced, and the immunoreactivity for the antibodies against the cysteine-rich/C-terminal domains of dystrophin was absent in the sarcolemma. Reverse transcriptase polymerase chain reaction analysis of the dystrophin gene revealed a complete lack of exons 71 through 74. In skeletal muscle, only the mutant gene was expressed. These results suggest that the patient is a symptomatic Duchenne muscular dystrophy carrier with skewed X-inactivation. This patient illustrates for the first time that a dystrophin abnormality can cause a secondary deficiency of merosin in dystrophinopathy. The reduction of merosin may account for the clinical phenotype of CMD and correlate with the white matter abnormalities in our patient.
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PMID:Deficiency of syntrophin, dystroglycan, and merosin in a female infant with a congenital muscular dystrophy phenotype lacking cysteine-rich and C-terminal domains of dystrophin. 927 Jun

The basal lamina of muscle fibers plays a crucial role in the development and function of skeletal muscle. An important laminin receptor in muscle is integrin alpha7beta1D. Integrin beta1 is expressed throughout the body, while integrin alpha7 is more muscle-specific. To address the role of integrin alpha7 in human muscle disease, we determined alpha7 protein expression in muscle biopsies from 117 patients with unclassified congenital myopathy and congenital muscular dystrophy by immunocytochemistry. We found three unrelated patients with integrin alpha7 deficiency and normal laminin alpha2 chain expression. To determine if any of these three patients had mutations of the integrin alpha7 gene, ITGA7, we cloned and sequenced the full-length human ITGA7 cDNA, and screened the patients for mutations. One patient had splice mutations on both alleles; one causing a 21-bp insertion in the conserved cysteine-rich region, and the other causing a 98-bp deletion. A second patient was a compound heterozygote for the same 98-bp deletion, and had a 1-bp frame-shift deletion on the other allele. A third showed marked deficiency of ITGA7 mRNA. Clinically, these patients showed congenital myopathy with delayed motor milestones. Our results demonstrate that mutations in ITGA7 are involved in a form of congenital myopathy.
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PMID:Mutations in the integrin alpha7 gene cause congenital myopathy. 1926 Sep 34

Four of the currently recognized autosomal recessive limb-girdle muscular dystrophies (LGMD type 2C-F) are caused by mutations in the genes encoding components of the sarcoglycan complex. LGMD 2C, caused by mutations in gamma-sarcoglycan, is prevalent in northern Africa, especially in Tunisia, where this type of muscular dystrophy was originally described. Although the disease initially was assumed to be genetically homogeneous in this region, linkage to the alpha-sarcoglycan locus (LGMD 2D) has also been found. We have now identified the first Tunisian family with beta-sarcoglycanopathy (LGMD 2E), further adding to the genetic heterogeneity of autosomal recessive LGMD in this population. Direct sequencing of the beta-sarcoglycan gene revealed a homozygous mutation (G272-->T, Arg91Leu) in exon 3. This change affects the same arginine residue in the immediate extracellular domain of the protein that was mutated to a proline (G272-->C, Arg91Pro) in a Brazilian family with a severe form of the disease. Immunohistochemical analysis for the sarcoglycan complex demonstrates absence of the known components of the complex in both of these families. We postulate that the immediate extracellular domain of beta-sarcoglycan may be important for the assembly and/or maintenance of this complex, potentially mediated by disulfide-bond formation to another sarcoglycan via the single cysteine residue in that domain.
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PMID:LGMD 2E in Tunisia is caused by a homozygous missense mutation in beta-sarcoglycan exon 3. 963 1

Calpain I (mu-calpain) and II (m-calpain) are well known calcium-activated neutral cysteine proteases. Many reports have shown that activation of calpain is related to cataract formation, neuronal degeneration, blood clotting, ischemic injuries, muscular dystrophy and cornified cell envelope (CE) formation. Here, we report that insoluble CE formation was reduced after treatment with calpain I inhibitor (N-acetyl-leucyl-leucyl-norleucinal) on normal human epidermal keratinocytes (NHEK), whereas serine and thiol protease inhibitors had no effect on the reduction of CE. When NHEK cells were confluent, keratinocytes were treated with various concentrations (0.5 microM-0.5 mM) of calpain I inhibitor or serine and thiol protease inhibitors under calcium induced differentiation. Insoluble CE formation was reduced about 90% in the 50 microM calpain inhibitor I treated group by day 9 of culture, whereas insoluble CE was reduced only 10% in the same condition. Interestingly TGase activity was blocked by 90% in the 0.5 mM calpain inhibitor treated group within 72 h, whereas TGase activity was retained by 80% in the 0.5 mM serine protease inhibitor treated group at 7 day treatment. Therefore it can be suggested that cysteine protease calpains might be responsible for the activation of the TGase 1 enzyme to complete insoluble CE formation during epidermal differentiation.
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PMID:Calpain inhibitors reduce the cornified cell envelope formation by inhibiting proteolytic processing of transglutaminase 1. 989 58

Skeletal muscle dystrophin is a 427 kDa protein thought to act as a link between the actin cytoskeleton and the extracellular matrix. Perturbations of the dystrophin-associated complex, for example, between dystrophin and the transmembrane glycoprotein beta-dystroglycan, may lead to muscular dystrophy. Previously, the cysteine-rich region and first half of the carboxy-terminal domain of dystrophin were shown to interact with beta-dystroglycan through a stretch of fifteen amino acids at the carboxy-terminus of beta-dystroglycan. This region of dystrophin implicated in binding beta-dystroglycan contains four modular protein domains: a WW domain, two putative Ca2+-binding EF-hand motifs, and a putative zinc finger ZZ domain. The WW domain is a globular domain of 38-40 amino acids with two highly conserved tryptophan residues spaced 20-22 amino acids apart. A subset of WW domains was shown to bind ligands that contain a Pro-Pro-x-Tyr core motif (where x is any amino acid). Here we elucidate the role of the WW domain of dystrophin and surrounding sequence in binding beta-dystroglycan. We show that the WW domain of dystrophin along with the EF-hand motifs binds to the carboxy-terminus of beta-dystroglycan. Through site-specific mutagenesis and in vitro binding assays, we demonstrate that binding of dystrophin to the carboxy-terminus of beta-dystroglycan occurs via a beta-dystroglycan Pro-Pro-x-Tyr core motif. Targeted mutagenesis of conserved WW domain residues reveals that the dystrophin/beta-dystroglycan interaction occurs primarily through the WW domain of dystrophin. Precise mapping of this interaction could aid in therapeutic design.
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PMID:The WW domain of dystrophin requires EF-hands region to interact with beta-dystroglycan. 1035 29

Two membrane proteins express the antigens that comprise the Kell blood group system. A single antigen, Kx, is carried on XK, a 440-amino acid protein that spans the membrane 10 times, and more than 20 antigens reside on Kell, a 93-kd, type II glycoprotein. XK and Kell are linked, close to the membrane surface, by a single disulfide bond between Kell cysteine 72 and XK cysteine 347. Although primarily expressed in erythroid tissues, Kell and XK are also present in many other tissues. The polymorphic forms of Kell are due to single base mutations that encode different amino acids. Some Kell antigens are highly immunogenic and may cause strong reactions if mismatched blood is transfused and severe fetal anemia in sensitized mothers. Antibodies to KEL1 may suppress erythropoiesis at the progenitor level, leading to fetal anemia. The cellular functions of Kell/XK are complex. Absence of XK, the McLeod phenotype, is associated with acanthocytic red blood cells (RBCs), and with late-onset forms of muscular dystrophy and nerve abnormalities. Kell, by homology, is a member of the neprilysin (M13) family of membrane zinc endopeptidases and it preferentially activates endothelin-3 by specific cleavage of the Trp21-Ile22 bond of big endothelin-3.
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PMID:The Kell blood group system: Kell and XK membrane proteins. 1079 80

Calpain 3 is known as the skeletal muscle-specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases. It was previously shown that defects in the human calpain 3 gene are responsible for limb girdle muscular dystrophy type 2A (LGMD2A), an inherited disease affecting predominantly the proximal limb muscles. To better understand the function of calpain 3 and the pathophysiological mechanisms of LGMD2A and also to develop an adequate model for therapy research, we generated capn3-deficient mice by gene targeting. capn3-deficient mice are fully fertile and viable. Allele transmission in intercross progeny demonstrated a statistically significant departure from Mendel's law. capn3-deficient mice show a mild progressive muscular dystrophy that affects a specific group of muscles. The age of appearance of myopathic features varies with the genetic background, suggesting the involvement of modifier genes. Affected muscles manifest a similar apoptosis-associated perturbation of the IkappaBalpha/nuclear factor kappaB pathway as seen in LGMD2A patients. In addition, Evans blue staining of muscle fibers reveals that the pathological process due to calpain 3 deficiency is associated with membrane alterations.
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PMID:Loss of calpain 3 proteolytic activity leads to muscular dystrophy and to apoptosis-associated IkappaBalpha/nuclear factor kappaB pathway perturbation in mice. 1113 85

The calpains form a growing family of structurally related intracellular multidomainal cysteine proteinases, which exhibit a catalytic domain distantly related to papain. In contrast to papain, however, their activity in most cases depends on calcium. The calpains are believed to play important roles in cytoskeletal remodeling processes, cell differentiation, apoptosis and signal transduction, but have also been implicated in muscular dystrophy, ischemia, traumatic brain injury, neurodegenerative diseases, rheumatoid arthritis and cataract formation. The best characterized calpains are the ubiquitously expressed mu- and m-calpains, consisting of a common 30 kDa small S-subunit (domains V and VI) and slightly differing 80 kDa large L-subunits (domains I to IV). We have recently determined the 2.3 A structure of recombinant full-length human m-calpain in the absence of calcium, which reveals that the catalytic domain and the two calmodulin-like domains, previously believed to represent the unique calcium switch, are not positioned adjacent to each other, but are separated by the beta-sandwich domain III, which distantly resembles C2 domains. Although the catalytic domain of apocalpain is strongly disrupted compared to papain (which explains its inactivity in the absence of calcium), the crystal structure reveals several sites where calcium could bind, thereby causing a subdomain fusion to form a papain-like catalytic center. All current evidence points to the cooperative interaction of several calcium binding sites. Sites identified include the three EF-hand binding sites in each calmodulin-like domain, the negatively charged segments arranged around the active-site cleft (provided by both catalytic subdomains), as well as an exposed acidic loop of domain III, whose charge compensation could allow the adjacent barrel-like subdomain IIb to move toward the helical subdomain IIa. The Gly-rich S-chain N-terminus and the calcium-loaded acidic loop could target the conventional calpains to cellular/nuclear membranes, thereby explaining their strongly reduced calcium requirement in vivo and in vitro in the presence of acidic phospholipids.
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PMID:Structural basis for possible calcium-induced activation mechanisms of calpains. 1151 28

The calpains form a growing family of structurally related intracellular multidomain cysteine proteinases containing a papain-related catalytic domain, whose activity depends on calcium. The calpains are believed to play important roles in cytoskeletal remodeling processes, cell differentiation, apoptosis and signal transduction, but are also implicated in muscular dystrophy, cardiac and cerebral ischemia, platelet aggregation, restenosis, neurodegenerative diseases, rheumatoid arthritis and cataract formation. The best characterized calpains, the ubiquitously expressed mu- and m-calpains, are heterodimers consisting of a common 30-kDa small and a variable 80-kDa subunit. The recently determined crystal structures of human and rat m-calpain crystallized in the absence of calcium essentially explain the inactivity of the apoform by catalytic domain disruption, indicate several sites where calcium could bind causing reformation of a papain-like catalytic domain, and additionally reveal modes by which phospholipid membranes could reduce the calcium requirement. Current evidence points to a cooperative interaction of several sites, which, upon calcium binding, trigger the reformation of a papain-similar catalytic domain.
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PMID:The structure of calcium-free human m-calpain: implications for calcium activation and function. 1167 52

The ex vivo effects of passive mechanical stretch on the activation of nuclear factor-kappaB (NF-kappaB) pathways in skeletal muscles from normal and mdx mouse, a model of Duchenne muscular dystrophy (DMD), were investigated. The NF-kappaB/DNA binding activity of the diaphragm muscle was increased by the application of axial mechanical stretch in a time-dependent manner. The increased activation of NF-kappaB was associated with a concomitant increase in I-kappaB (IkappaB) kinase activity and the degradation of IkappaBalpha protein. Pretreatment of the muscles with nifedipine (a Ca2+ channel blocker) and gadolinium(III) chloride (a stretch-activated channel blocker) did not alter the level of activation of NF-kappaB, ruling out involvement of Ca2+ influx through these channels. Furthermore, N-acetyl cysteine, a free radical inhibitor, blocked the mechanical stretch-induced NF-kappaB activation, suggesting the involvement of free radicals. Compared with normal diaphragm, the basal level of NF-kappaB activity was higher in muscles from mdx mice, and it was further enhanced in mechanically stretched muscles. Furthermore, activation of NF-kappaB and increased expression of inflammatory cytokines IL-1beta and tumor necrosis factor alpha in the mdx mouse precede the onset of muscular dystrophy. Our results show that mechanical stretch activates the classical NF-kappaB pathway and this pathway could be predominately active in DMD.
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PMID:Mechanical stress activates the nuclear factor-kappaB pathway in skeletal muscle fibers: a possible role in Duchenne muscular dystrophy. 1263 78


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