Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.54 (calpain 3)
 430 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysferlin is the protein product of the DYSF gene mapped at 2p31, which mutations cause limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. To date, nine autosomal recessive forms (AR-LGMD) have been identified: four genes, which code for the sarcoglycan glycoproteins, are associated with both mild and severe forms, the sarcoglycanopathies (LGMD2C, 2D, 2E and 2F). The other five forms, usually causing a milder phenotype are LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2G (telethonin), LGMD2H (9q31-11), and LGMD21 (19q13.3). We studied dysferlin expression in a total of 176 patients, from 166 LGMD families: 12 LGMD2B patients, 70 with other known forms of muscular dystrophies (LGMD2A, sarcoglycanopathies, LGMD2G), in an attempt to assess the effect of the primary gene-product deficiency on dysferlin. In addition, 94 still unclassified LGMD families were screened for dysferlin deficiency. In eight LGMD2B patients from five families, no dysferlin was observed in muscle biopsies, both through immunofluorescence (IF) and Western blot methodologies, while in two families, a very faint band was detected. Both patterns, negative or very faint bands, were concordant in patients belonging to the same families, suggesting that dysferlin deficiency is specific to LGMD2B. Myoferlin, the newly identified homologue of dysferlin was studied for the first time in LGMD2B patients. Since no difference was observed between patients mildly and severely affected, this protein do not seem to modify the phenotype in the present dysferlin-deficient patients. Dystrophin, sarcoglycans, and telethonin were normal in all LGMD2B patients, while patients with sarcoglycanopathies (2C, 2D, and 2E), LGMD2A, LGMD2G, and DMD showed the presence of a normal dysferlin band by Western blot and a positive pattern on IF. These data suggest that there is no interaction between dysferlin and these proteins. However, calpain analysis showed a weaker band in four patients from two families with intra-familial concordance. Therefore, this secondary deficiency of calpain in LGMD2B families, may indicate an interaction between dysferlin and calpain in muscle. Dysferlin was also present in cultured myotubes, in chorionic villus, and in the skin. Dysferlin deficiency was found in 24 out of a total of 166 Brazilian AR-LGMD families screened for muscle proteins (approximately 14%), thus representing the second most frequent known LGMD form, after calpainopathy, in our population.
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PMID:Dysferlin protein analysis in limb-girdle muscular dystrophies. 1166 64

Muscular dystrophy with myositis (mdm) is a recessive mouse mutation that causes severe and progressive muscular degeneration. Here we report the identification of the mdm mutation as a complex rearrangement that includes a deletion and a LINE insertion in the titin (Ttn) gene. Mutant allele-specific splicing results in the deletion of 83 amino acids from the N2A region of TTN, a domain thought to bind calpain-3 (CAPN3) the product of the human limb-girdle muscular dystrophy type 2A (LGMD2A) gene. The Ttn(mdm) mutant mouse may serve as a model for human tibial muscular dystrophy, which maps to the TTN locus at 2q31 and shows a secondary reduction of CAPN3 similar to that observed in mdm skeletal muscle. This is the first demonstration that a mutation in Ttn is associated with muscular dystrophy and provides a novel animal model to test for functional interactions between TTN and CAPN3.
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PMID:The muscular dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin. 1182 83

p94 belongs to the calpain family of enzymes, also called calcium-activated neutral proteases and is mainly expressed in the skeletal muscle. Mutations affecting the gene coding for p94 are responsible for a myopathy syndrome called Limb Girdle Muscular Dystrophy type 2A (LGMD2A). Although the activity of p94 seems necessary for muscle function, the biological role of the enzyme is still unknown. The goal of this study was to develop a muscle cell line in which the expression level of p94 can be regulated, by an inducible way. In this study, a biological system was developed which allowed mimicking, in vitro, of part of the events occurring in patients (i.e. a decrease of p94 activity). The first results indicate that the decrease in p94 activity results in a significant increase of myogenin level, a high specific transcription factor involved in myoblast fusion. This muscle specific inducible system is an interesting biological tool to assess specifically p94 function(s) in cultured muscle cells. According to the present results, p94 seems at least to be involved in a myogenesis regulation pathway via its action on certain proteins belonging to the myogenic regulator factor family.
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PMID:Development of an inducible system to assess p94 (CAPN3) function in cultured muscle cells. 1204 55

Limb-girdle muscular dystrophy, type 2A (LGMD 2A), is an autosomal recessive disorder that causes late-onset muscle-wasting, and is due to mutations in the muscle-specific protease calpain 3 (C3). Although LGMD 2A would be a feasible candidate for gene therapy, the reported instability of C3 in vitro raised questions about the potential of obtaining a stable, high-level expression of C3 from a transgene in vivo. We have generated transgenic (Tg) mice with muscle-specific overexpression of full-length C3 or C3 isoforms, which arise from alternative splicing, to test whether stable expression of C3 transgenes could occur in vivo. Unexpectedly, we found that full-length C3 can be overexpressed at high levels in vivo, without toxicity. In addition, we found that Tg expressing C3 lacking exon 6, an isoform expressed embryonically, have muscles that resemble regenerating or developing muscle. Tg expressing C3 lacking exon 15 shared this morphology in the soleus, but not other muscles. Assays of inflammation or muscle membrane damage indicated that the Tg muscles were not degenerative, suggesting that the immature muscle resulted from a developmental block rather than degeneration and regeneration. These studies show that C3 can be expressed stably in vivo from a transgene, and indicate that alternatively spliced C3 isoforms should not be used in gene-therapy applications because they impair proper muscle development.
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PMID:Stable expression of calpain 3 from a muscle transgene in vivo: immature muscle in transgenic mice suggests a role for calpain 3 in muscle maturation. 1208 32

In our laboratory, limb-girdle muscular dystrophy (LGMD) accounted for 20% of all patients with muscular dystrophy. To determine the incidence of various forms of LGMD phenotypes, we looked for mutations in the calpain 3 gene and, for deficiencies in dysferlin and sarcoglycan by immunohistochemical studies with specific antibodies on muscle biopsies from patients with probable autosomal recessive inheritance (LGMD2), which were mostly sporadic cases of LGMD. Fourteen of 276 (5%) patients examined had sarcoglycan complex deficiency (sarcoglycanopathy) and 21 of 80 (26%) had mutations in the calpain 3 gene. Although we have not performed gene analysis in all patients, 10 of 64 (15%) patients examined had no apparent immunoreactivity against the dysferlin antibody. Thus, approximately 46% of LGMD2 patients had the above 3 distinct disorders, but in 54% the causative defects remain unknown.
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PMID:[Recent advances in limb-girdle muscular dystrophy research]. 1223 36

Telethonin is a 19-kDa sarcomeric protein, localized to the Z-disc of skeletal and cardiac muscles. Mutations in the telethonin gene cause limb-girdle muscular dystrophy type 2G (LGMD2G). We investigated the sarcomeric integrity of muscle fibers in LGMD2G patients, through double immunofluorescence analysis for telethonin with three sarcomeric proteins: titin, alpha-actinin-2, and myotilin and observed the typical cross striation pattern, suggesting that the Z-line of the sarcomere is apparently preserved, despite the absence of telethonin. Ultrastructural analysis confirmed the integrity of the sarcomeric architecture. The possible interaction of telethonin with other proteins responsible for several forms of neuromuscular disorders was also analyzed. Telethonin was clearly present in the rods in nemaline myopathy (NM) muscle fibers, confirming its localization to the Z-line of the sarcomere. Muscle from patients with absent telethonin showed normal expression for the proteins dystrophin, sarcoglycans, dysferlin, and calpain-3. Additionally, telethonin showed normal localization in muscle biopsies from patients with LGMD2A, LGMD2B, sarcoglycanopathies, and Duchenne muscular dystrophy (DMD). Therefore, the primary deficiency of calpain-3, dysferlin, sarcoglycans, and dystrophin do not seem to alter telethonin expression.
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PMID:Telethonin protein expression in neuromuscular disorders. 1237 11

We have performed expression profiling to define the molecular changes in dysferlinopathy using a novel dedicated microarray platform made with 3'-end skeletal muscle cDNAs. Eight dysferlinopathy patients, defined by western blot, immunohistochemistry and mutation analysis, were investigated with this technology. In a first experiment RNAs from different limb-girdle muscular dystrophy type 2B patients were pooled and compared with normal muscle RNA to characterize the general transcription pattern of this muscular disorder. Then the expression profiles of patients with different clinical traits were independently obtained and hierarchical clustering was applied to discover patient-specific gene variations. MHC class I genes and genes involved in protein biosynthesis were up-regulated in relation to muscle histopathological features. Conversely, the expression of genes codifying the sarcomeric proteins titin, nebulin and telethonin was down-regulated. Neither calpain-3 nor caveolin, a sarcolemmal protein interacting with dysferlin, was consistently reduced. There was a major up-regulation of proteins interacting with calcium, namely S100 calcium-binding proteins and sarcolipin, a sarcoplasmic calcium regulator.
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PMID:Gene expression profiling in dysferlinopathies using a dedicated muscle microarray. 1247 Oct 55

Defects in human calpain 3 are responsible for limb-girdle muscular dystrophy type 2A, an autosomal-recessive disorder characterized mainly by late-onset proximal muscular atrophy. A corresponding murine model has previously been generated by gene targeting. In this report, muscular activity of calpain 3-deficient (capn3(-/-)) mice was evaluated at different ages. Growth curves showed a progressive global muscular atrophy. Histological examination throughout the lifespan of mice confirmed the dystrophic lesions. Whole animal tests showed only a mild significant impairment of the forelimbs. Studies of the mechanical properties of selected isolated fast- and slow-twitch muscles demonstrated that slow-twitch muscles were significantly weaker in capn3(-/-) mice than in wild-type mice. Three different tests showed that there was no membrane disruption, suggesting a nonmechanical etiology of capn3(-/-) mice dystrophy. These findings are consistent with a mechanism involving signaling systems.
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PMID:Force impairment in calpain 3-deficient mice is not correlated with mechanical disruption. 1270 83

Calpain 3/p94, the skeletal muscle-specific isoform of the calpain large subunit family, is a protein product of the gene responsible for limb-girdle muscular dystrophy type 2A (LGMD2A). Through yeast two-hybrid experiments, calpain 3 has been shown to bind to titin in myofibrils [Sorimachi et al. (1995) J. Biol. Chem. 270, 31158-31162]. However, because of extensive autolysis activity, calpain 3 localization in skeletal muscle has been undefined. In this study, we generated a polyclonal antibody against an N-terminal 98-amino-acid calpain 3 fragment, which is not homologous to the corresponding regions of other conventional calpains. This antibody stained myofibrils with a unique repeated doublet-pattern. Confocal microscopic observation with marker antibodies confirmed that calpain 3 is localized in the N2 region of myofibrils. Furthermore, using this antibody, we examined the localization of calpain 3 in LGMD2A muscles.
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PMID:Localization of calpain 3 in human skeletal muscle and its alteration in limb-girdle muscular dystrophy 2A muscle. 1280 18

Calpain, a Ca(2+)-requiring cytoplasmic cysteine protease, plays indispensable roles in various cellular functions such as signal transduction, cell growth and differentiation, apoptosis, necrosis, and so on. Although most of the detailed physiological functions of calpains have not yet been elucidated, the importance of calpain is obvious from the increasing numbers of papers describing relationships between human disease states (such as Alzheimer's disease, cataract, and muscular dystrophies) and malfunction of calpain. One of the recent remarkable topics of calpain is that a single nucleotide polymorphism of CAPN10, the gene for calpain 10, is related to type 2 diabetes. However, physiological functions of calpain 10 and its relation to diabetes are still unclear. Among 14 human calpain genes, mutations in CAPN3, the gene for p94/calpain 3a and Lp82/calpain 3b, are the only example that genetically connects the calpain gene and human disease, in this case, limb-girdle muscular dystrophy type 2A (LGMD2A). p94 has unique characteristics such as apparent Ca(2+)-independent activation and very rapid autolytic activity, which are dependent on p94-specific regions, NS, IS1, and IS2. Based on the 3D structures of micro - and m-calpain, molecular functions of p94 in relation to LGMD2A are discussed, with the hope of providing us with some clues to understand calpain functions and its relationships to human diseases.
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PMID:[Calpain and pathology in view of structure-function relationships]. 1284 69


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