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

The abundance of mRNAs transcribed from human genes of the calpain superfamily was studied in 72 human tissues and cell types by the Human Multiple Tissue Expression (MTE) Array technique. The analysis included the large subunits of mu- and m-calpains, the small subunits, calpastatin and calpain 3 (p94). Besides specific data on transcriptional activity, two major conclusions emerged: (i) 'ubiquitous' calpains are not expressed in all cell types, and (ii) a 'tissue-specific' calpain may be expressed in many cell types apart from the one in which it is particularly abundant. Therefore, the categoric classification of 'ubiquitous' vs. 'tissue-specific' calpains is a simplification.
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PMID:Revisiting ubiquity and tissue specificity of human calpains. 1288 62

Limb girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the calpain 3 gene. In a large family affected by LGMD2A with four severely affected members, three additional asymptomatic relatives had very high serum creatine kinase concentrations. All were homozygous for the R110X mutation and showed a total absence of calpain 3 in the muscle. Histological analysis of muscle in these three rare preclinical cases showed a consistent but unusual pattern, with isolated fascicles of degenerating fibres in an almost normal muscle. This pattern was also seen in one patient with early stage LGMD2A who had a P82L missense mutation and a partial deficiency of calpain 3 in the muscle, but was not seen in early stage patients affected by other forms of LGMD. These findings suggest that a peculiar pattern of focal degeneration occurs in calpainopathy, independently of the type of mutation or the amount of calpain 3 in the muscle.
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PMID:The effect of calpain 3 deficiency on the pattern of muscle degeneration in the earliest stages of LGMD2A. 1289 Aug 17

p94 (also called calpain 3) is the skeletal muscle-specific calpain and is considered to be a "modulator protease" in various cellular processes. Analysis of p94 at the protein level is an urgent issue because the loss of p94 protease activity causes limb-girdle muscular dystrophy type 2A. In this study, we enzymatically characterized one alternatively spliced variant of p94, p94:exons 6(-)15(-)16(-) (p94delta), which lacks two of the p94-specific insertion sequences. In contrast to p94, which has hardly been studied enzymatically due to its rapid, thorough, and apparently Ca(2+)-independent autolytic activity, p94delta was stably expressed in COS and insect cells. p94delta showed Ca(2+)-dependent caseinolytic and autolytic activities and an inhibitor spectrum similar to those of the conventional calpains. However, calpastatin did not inhibit p94delta and is a substrate for p94delta, which is consistent with the properties of p94, presenting p94 as a possible regulator of the conventional calpain system. We also established a semi-quantitative fluorescence resonance energy transfer assay using the calpastatin sequence specifically to measure p94 activity. This method detects the activity of COS-expressed p94 and p94delta, suggesting that it has potential to evaluate p94 activity in vivo and in the diagnosis of limb-girdle muscular dystrophy type 2A.
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PMID:Possible regulation of the conventional calpain system by skeletal muscle-specific calpain, p94/calpain 3. 1459 50

There are two classes of an intracellular 'modulator protease', calpain: ubiquitous and tissue-specific. p94/calpain 3 is an example of the latter, predominantly expressed in muscle. A defect in the p94 gene causes muscular dystrophy. Here we report that human and mouse p94 genes have a possible novel alternative promoter expressing p94 variants in all tissues examined including human lens epithelial cells. The possible promoter region and the following novel exons overlap the 3' region of the neutral alpha-glucosidase C gene. Unlike p94, the novel p94 variants expressed in COS7 cells do not undergo rapid autolysis, suggesting basic functions different from p94.
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PMID:Newly identified exons encoding novel variants of p94/calpain 3 are expressed ubiquitously and overlap the alpha-glucosidase C gene. 1467 85

In this study, we generated three SAGE libraries from melanoma tissues. Using bioinformatics tools usually applied to microarray data, we identified several genes, including novel transcripts, which are preferentially expressed in melanoma. SAGE results converged with previous microarray analysis on the importance of intracellular calcium and G-protein signaling, and the Wnt/Frizzled family. We also examined the expression of CD74, which was specifically, albeit not abundantly, expressed in the melanoma libraries using a melanoma progression tissue microarray, and demonstrate that this protein is expressed by melanoma cells but not by benign melanocytes. Many genes involved in intracellular calcium and G-protein signaling were highly expressed in melanoma, results we had observed earlier from microarray studies (Bittner et al., 2000). One of the genes most highly expressed in our melanoma SAGE libraries was a calcium-regulated gene, calpain 3 (p94). Immunohistochemical analysis demonstrated that calpain 3 moves from the nuclei of non-neoplastic cells to the cytoplasm of malignant cells, suggesting activation of this intracellular proteinase. Our SAGE results and the clinical validation data demonstrate how SAGE profiles can highlight specific links between signaling pathways as well as associations with tumor progression. This may provide insights into new genes that may be useful for the diagnosis and therapy of melanoma.
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PMID:Generation and analysis of melanoma SAGE libraries: SAGE advice on the melanoma transcriptome. 1475 46

Mutations in the calpain 3 (CAPN3) gene are responsible for limb-girdle muscular dystrophy (LGMD) type 2A. We report five causal mutations: 550delA, DeltaFWSAL, R541W, Y357X and R49H found on 45/50 of alleles studied in 25 unrelated families from Croatia. The 550delA mutation was present on 76% of CAPN3 chromosomes that led us to screen general population for this mutation; 532 random blood samples from three different regions were analyzed using allele-specific PCR. Four healthy 550delA heterozygous were found suggesting a frequency of 1 in 133. All four carriers detected originated from an island and mountain region close to the Adriatic Sea. These findings combined with haplotype analysis confirm that our general population is rather "closed" with a probable founder effect in some parts of the country. In addition, the high frequency of 550delA mutation found in some neighboring European countries together with the easy detection of the 550delA mutation should streamline genetic analysis, especially bearing in mind the geographic and ethnic origin of the patients. Our results, combined with published haplotype studies suggest that 550delA originated in the Eastern Mediterranean from which it has probably spread widely across Europe. Extending this study to other areas would help to address this epidemiological question. Our data are relevant to accurate genetic counseling and patient testing since we lack sensitive and specific biopsy screening methods for detecting patients with calpainopathy. Thus, detection of patients relies on the direct detection of gene mutation and our findings may be helpful in establishing diagnostic screening strategy.
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PMID:Prevalence of the 550delA mutation in calpainopathy (LGMD 2A) in Croatia. 1498 15

We report on two siblings with late-onset, limb-girdle muscular dystrophy (LGMD) inherited in an autosomal recessive manner. The LGMD was characterized by many rimmed vacuoles and reduced expression of the laminin beta1 chain in skeletal muscle. Both patients developed a progressive wasting and weakness of limb-girdle muscles in the late forties or early fifties; their facial, ocular, bulbar, and cardiac muscles were not involved. Histopathology of skeletal muscles biopsies showed typical dystrophic changes with many rimmed vacuoles. The immunoreactivity of the laminin beta1 chain was reduced in the muscle fibers, while dystrophin, sarcoglycans, beta-dystroglycan, dysferlin, and other laminin components were normally expressed. A mutation search revealed that no mutation existed in the coding region of the calpain 3, telethonin and UDP-N-acetylglucosamine 2-epimerase/N-acetylmanosamine kinase (GNE) genes. We conclude that this autosomal recessive LGMD is unknown and characterized by its late onset, rimmed vacuoles and reduction of the laminin beta1 chain in muscle fibers.
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PMID:Late-onset autosomal recessive limb-girdle muscular dystrophy with rimmed vacuoles. 1500 3

The physiological role of the skeletal muscle-specific calpain 3, p94, is presently unknown, but defects in its gene cause limb girdle muscular dystrophy type 2A. This calcium-dependent cysteine protease resembles the large subunit of m-calpain but with three unique additional sequences: an N-terminal region (NS), and two insertions (IS1 and IS2). The latter two insertions have been linked to the chronic instability of the whole enzyme both in vivo and in vitro. We have shown previously that the core of p94 comprising NS, domains I and II, and IS1 is stable as a recombinant protein in the absence of Ca(2+) and undergoes autolysis in its presence. Here we show that p94I-II cannot hydrolyze an exogenous substrate before autolysis but is increasingly able to do so when autolysis proceeds for several hours. This gain in activity is caused by cleavage of IS1 during autolysis because a deletion mutant lacking the NS region (p94I-II DeltaNS) shows the same activation profile. Similarly, the calpain inhibitors E-64 and leupeptin have almost no inhibitory effect on substrate hydrolysis by p94I-II soon after calcium addition but cause complete inhibition when autolysis progresses for several hours. As autolysis proceeds, there is release of the internal IS1 peptide, but the two portions of the core remain tightly associated. Modeling of p94I-II suggests that IS1 contains an amphipathic alpha-helix flanked by extended loops. The latter are the targets of autolysis and limited digestion by exogenous proteases. The presence and location of the alpha-helix in recombinant IS1 were confirmed by circular dichroism and by the introduction of a L286P helix-disrupting mutation. Within p94I-II, L286P caused premature autoproteolysis of the enzyme. IS1 is an elaboration of a loop in domain II near the active site, and it acts as an internal autoinhibitory propeptide, blocking the active site of p94 from substrates and inhibitors.
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PMID:Insertion sequence 1 of muscle-specific calpain, p94, acts as an internal propeptide. 1507 71

The giant protein titin serves a primary role as a scaffold for sarcomere assembly; however, proteins that mediate this remodeling have not been identified. One potential mediator of this process is the protease calpain 3 (C3), the protein mutated in limb girdle muscular dystrophy type 2A. To test the hypothesis that C3 mediates remodeling during myofibrillogenesis, C3 knockout (C3KO) mice were generated. The C3KO mice were atrophic containing small foci of muscular necrosis. Myogenic cells fused normally in vitro, but lacked well-organized sarcomeres, as visualized by electron microscopy (EM). Titin distribution was normal in longitudinal sections from the C3KO mice; however, EM of muscle fibers showed misaligned A-bands. In vitro studies revealed that C3 can bind and cleave titin and that some mutations that are pathogenic in human muscular dystrophy result in reduced affinity of C3 for titin. These studies suggest a role for C3 in myofibrillogenesis and sarcomere remodeling.
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PMID:Null mutation of calpain 3 (p94) in mice causes abnormal sarcomere formation in vivo and in vitro. 1513 96

Calpains are calcium-modulated proteases which respond to Ca2+ signals by removing limited portions of protein substrates, thereby irreversibly modifying their function(s). Members of this protease family are present in a variety of organisms ranging from mammals to plants; some of them are ubiquitously expressed, while others are tissue specific. Although calpains are apparently involved in a multitude of physiological and pathological events, their functions are still poorly understood. In two cases, however, the alteration of a member of the calpain family has been clearly identified as being responsible for a human disease: the loss of function of calpain 3 causes limb girdle muscular dystrophy type 2A, and mutations in the gene coding for calpain 10 have been shown to correlate with non-insulin-dependent diabetes.
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PMID:Calpain-related diseases. 1533 56


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