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)

A branch of a highly inbred family was referred for prenatal counseling with an initial misdiagnosis of Becker Muscular Dystrophy (BMD) due to the limited clinical and laboratory data obtained in pre-dystrophin era and hidden family information. In a second branch of the family with a diagnosis of limb-girdle muscular dystrophy type 2A (LGMD2A) molecular studies revealed a homozygous 550 delta A mutation in the calcium-activated neutral protease 3 (calpain 3, CANP3) gene in the affected members. Finally, in the third branch of the family, it turned out that both parents were heterozygous for the 550 delta A mutation and the 13-week-old fetus was homozygous. The same mutation subsequently also was found in the first branch of the family. The parents were informed that the risk of their child of developing the disease would be very high given that he was carrying the same homozygous mutation of the other affected members. They were informed also that in another population (in Reunion Island) the same disease does not necessarily follow such a simple pattern of inheritance. After counseling the parents decided to terminate the pregnancy.
 ...
PMID:Prenatal diagnosis of limb-girdle muscular dystrophy type 2A. 878 5

Major advances in the genetic understanding of the limb-girdle (LGMD) and congenital (CMD) muscular dystrophies have led to a new, genetically based classification of these disorders. The definition of the complex of dystrophin-associated proteins on a biochemical and subsequently genetic level has greatly accelerated this progress by providing candidate genes to complement or replace the process of linkage analysis either in families with muscular dystrophy or in sporadic cases. The major components of the dystrophin-associated proteins now known to be involved in muscular dystrophy besides dystrophin itself ar the sarcoglycan complex and the alpha 2-chain (merosin) of laminin-2 in the extracellular matrix. Mutations in the various sarcoglycans account for four types of autosomal recessive LGMD of varying severity (types 2C through 2F), including severe childhood-onset presentations. One type of autosomal recessive LGMD (type 2A) is caused by mutations in the protease calpain-3, whereas the gene for type 2B has not yet been identified, although the responsible locus has been assigned to chromosome 2p13. There are different autosomal dominant forms as well, one of which has been mapped to chromosome 5q31. With regard to CMDs, the major breakthrough involves a type of "classic" CMD with abnormalities of the white matter on magnetic resonance imaging of the brain. These patients show deficiencies of the laminin alpha 2-chain, and mutations in the corresponding gene have been identified. The group of laminin alpha 2-chain-positive classic CMD likely is heterogeneous. Among the group of CMDs with abnormalities of brain formation and mental retardation, genetic, immunohistochemical, and clinical differences are now beginning to emerge to help in the distinction between Fukuyama muscular dystrophy, the Walker-Warburg syndrome, and muscle-eye-brain disease.
 ...
PMID:Beyond dystrophin: current progress in the muscular dystrophies. 901 40

The limb-girdle muscular dystrophies are a genetically heterogeneous group of inherited progressive muscle disorders that affect mainly the proximal musculature, with evidence for at least three autosomal dominant and eight autosomal recessive loci. The latter mostly involve mutations in genes encoding components of the dystrophin-associated complex; another form is caused by mutations in the gene for the muscle-specific protease calpain 3. Using a positional cloning approach, we have identified the gene for a form of limb-girdle muscular dystrophy that we previously mapped to chromosome 2p13 (LGMD2B). This gene shows no homology to any known mammalian gene, but its predicted product is related to the C. elegans spermatogenesis factor fer-1. We have identified two homozygous frameshift mutations in this gene, resulting in muscular dystrophy of either proximal or distal onset in nine families. The proposed name 'dysferlin' combines the role of the gene in producing muscular dystrophy with its C. elegans homology.
 ...
PMID:A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. 973 27

Recent progress in the field of molecular genetics revealed a broader spectrum of dystrophin-related disorders than previously assumed. In addition, the pathogenetic basis of other types of muscular dystrophies could be identified: some autosomal-recessive limb girdle dystrophies are caused by mutations of sarcoglycan genes, others are caused by deficiency of the sarcoplasmatic enzyme calpain-3. Emery-Dreifuss muscular dystrophy is due to the deficiency of the nuclear membrane protein emerin. About 50% of congenital muscular dystrophies are related to mutations of a extracellular matrix protein merosin (alpha-laminin). A series of monoclonal antibodies for immunohistochemistry is now available recognizing many cytoskeletal muscle proteins. In combination with molecular genetics a diagnostic flow chart can be developed which allows a definite diagnosis in most cases. In this review disease entities are illustrated by case reports. We discuss the significance of immunohistochemical and molecular methods for diagnosis.
 ...
PMID:[Current diagnosis in muscular dystrophies. New developments, methods of examination and case examples]. 1009 43

A multiplex system of Western blotting is presented in which most of the current muscular dystrophy proteins can be analyzed simultaneously on one pair of blots. This represents a significant improvement in efficiency and cost for this type of analysis. The final diagnosis is more quickly achieved in patients where several possible diagnoses are indicated after clinical appraisal, and those with unusual presentations may be quickly resolved. The method uses a biphasic polyacrylamide gel system, which enables the corresponding blot to be probed simultaneously with a cocktail of monoclonal antibodies. The gel is optimized so that large proteins of more than 200 kd (eg, dystrophin, dysferlin, and myosin heavy chain) can be analyzed in the top part, while smaller proteins under 150 kd (eg, calpain 3, the 80-kd fragment of laminin alpha2 chain, all of the sarcoglycans, and caveolin 3) are separated in the lower phase. This basic system could be used for different combinations of antibodies as new muscular dystrophy proteins are identified and require examination. In addition, analysis of the laminin alpha2 chain of merosin showed that this protein was expressed as a doublet or triplet set of bands in many patients with active muscle pathology. This may indicate the existence of an embryonic isoform, which is re-expressed in regenerating fibers.
 ...
PMID:Multiplex Western blotting system for the analysis of muscular dystrophy proteins. 1023 40

The clinical heterogeneity which has long been recognized in the limb-girdle muscular dystrophies (LGMD) has been shown to relate to the involvement of a large number of different genes. At least eight forms of autosomal recessive LGMD and three forms of autosomal dominant disease are now recognized and can be defined by the primary gene or protein involved, or by a genetic localization. These advances have combined the approaches of positional cloning and candidate gene analysis to great effect, with the pivotal role of the dystrophin-associated complex confirmed through the involvement of at least four dystrophin-associated proteins in different subtypes of autosomal recessive LGMD (the sarcoglycanopathies). Two novel mechanisms may have to be postulated to explain the involvement of the calpain 3 and dysferlin genes in other forms of LGMD. Using the diagnostic tools which have become available as a result of this increased understanding, the clinical features of the various subtypes are also becoming clearer, with useful diagnostic and prognostic information at last available to the practising clinician.
 ...
PMID:Making sense of the limb-girdle muscular dystrophies. 1043 Aug 28

Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically heterogeneous group of disorders that affect mainly the proximal musculature. There are eight genetically distinct forms of AR LGMD, LGMD 2A-H (refs 2-10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mutations in the genes encoding calpain 3 (ref. 11) and dysferlin, respectively, and are usually associated with a mild phenotype. Mutations in the genes encoding gamma-(ref. 14), alpha-(ref. 5), beta-(refs 6,7) and delta (ref. 15)-sarcoglycans are responsible for LGMD 2C to 2F, respectively. Sarcoglycans, together with sarcospan, dystroglycans, syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course. The LGMD 2G locus maps to a 3-cM interval in 17q11-12 in two Brazilian families with a relatively mild form of AR LGMD (ref. 9). To positionally clone the LGMD 2G gene, we constructed a physical map of the 17q11-12 region and refined its localization to an interval of 1.2 Mb. The gene encoding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.
 ...
PMID:Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. 1065 62

This lecture traces recent advances in knowledge of the muscular dystrophies, as well as their increasing complexity. They are described through the eyes of the author from his first exposure to and complete ignorance of the disease in the late 1950s, through the advent of modern techniques, to the molecular genetic revolution, with the recognition of individual genes and proteins for disorders within the muscular dystrophy umbrella. There initially seemed to be a logical sequence of linked membrane proteins from dystrophin in Duchenne and Becker dystrophy, through the dystrophin-associated glycoproteins (sarcoglycans) in some of the limb girdle muscular dystrophies (LGMD), to the extracellular matrix protein merosin (alpha-2 laminin) in congenital muscular dystrophy (CMD). The first spoke in the wheel came with the discovery of a calcium activated protease enzyme, calpain 3, in one form of LGMD, and subsequently another novel non-membrane protein, dysferlin, in another. There are currently at least eight distinct genetic forms of LGMD alone, and another eight separate genetic entities in the CMD group. This has highlighted our ignorance of the pathogenesis of the muscular dystrophies in relation to a diverse array of protein deficiencies. To compound things further, the X-linked and dominant forms of Emery-Dreifuss muscular dystrophy have recently been linked to emerin and lamin A/C, respectively, two proteins of the nuclear membrane, opening up yet another new ballpark of discovery.
 ...
PMID:What is muscular dystrophy? Forty years of progressive ignorance. 1107 61

Labrador retrievers suffer from an autosomal recessive muscular dystrophy of unknown aetiology. Dogs affected with this disease develop generalized weakness associated with severe, generalized skeletal muscle atrophy and mild elevations in creatine kinase in the first few months of life. The severity of signs tends to progress over the first year of life but can vary from mild exercise intolerance to non-ambulatory tetraparesis. Beyond 1 year of age, the signs usually stabilize and although muscle mass does not increase, affected dogs' strength may improve slightly. The pathological changes present on muscle biopsy include marked variation in muscle fibre size with hypertrophied and round atrophied fibres present. There is an increased number of fibres with central nuclei and split fibres can be seen. It has been suggested that the disorder is a model for limb-girdle muscular dystrophy. In recent years, mutations in genes encoding the proteolytic enzyme, calpain 3, a novel protein named dysferlin, and components of the dystrophin-glycoprotein complex have been identified as causes of autosomal recessive limb-girdle muscular dystrophy. We have evaluated these proteins in normal dogs and in three Labrador retrievers with autosomal recessive muscular dystrophy using immunohistochemistry and Western blot analysis on frozen skeletal muscle. The results demonstrate that dystrophin, the sarcoglycans, alpha-actinin, dysferlin and calpain 3 are present in the normal and affected dogs. We conclude that this autosomal recessive muscular dystrophy is not due to a deficiency of alpha-actinin, or any of the known autosomal recessive limb-girdle muscular dystrophy proteins, although we cannot rule out a malfunction of any of these proteins.
 ...
PMID:Evaluation of the dystrophin-glycoprotein complex, alpha-actinin, dysferlin and calpain 3 in an autosomal recessive muscular dystrophy in Labrador retrievers. 1116 65

Reduced sarcolemmal integrity in dystrophin-deficient muscles of mdx mice and Duchenne muscular dystrophy (DMD) patients has been reported to result in altered calcium homeostasis. Previous studies have shown a correlative relationship between calcium-dependent protease (calpain) activity in dystrophic muscle and muscle necrosis, but have not tested whether calpain activation precedes cell death or is a consequence of it. To test a causal relationship between calpain activation and muscle cell death in dystrophin deficiency, mdx mice were generated that overexpress a calpastatin transgene in muscle. Calpastatin (CS) is a specific, endogenous inhibitor of m- and micro -calpains that does not inhibit calpain 3 (p94). CS overexpression on a C57/BL 10 background produced no phenotype. Transgenic (Tg) mice crossed with mdx mice were tested for pathological indicators of necrosis, regeneration and membrane damage. Two lines of mice were examined, with different levels of CS overexpression. Both lines of Tg/mdx mice showed reductions in muscle necrosis at 4 weeks of age. These mice had fewer as well as smaller lesions. In addition, one line of mice had significantly less regeneration, indicating a reduction in previous necrosis. The extent of improvement correlated with the level of CS protein expression. Membrane damage, as assessed by procion orange and creatine kinase assays, was unchanged, supporting the idea that calpains act downstream of the primary muscle defect. These data suggest that calpains play an active role in necrotic processes in dystrophic muscle and that inhibition of calpains might provide a good therapeutic option for treatment of DMD.
 ...
PMID:Overexpression of a calpastatin transgene in mdx muscle reduces dystrophic pathology. 1235 90


1 2 3 Next >>