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Jacques S. Beckmann - One of the best experts on this subject based on the ideXlab platform.

  • Limb-Girdle Muscular Dystrophy type 2A can result from accelerated autoproteolytic inactivation of calpain 3.
    Biochemistry, 2009
    Co-Authors: Christopher P. Garnham, Robert L. Campbell, Jacques S. Beckmann, Rachel Hanna, Jordan S. Chou, Kristin E. Low, Keith Gourlay, Peter L Davies
    Abstract:

    Loss-of-function mutations in calpain 3 have been shown to cause Limb-Girdle Muscular Dystrophy type 2A (LGMD2A), an autosomal recessive disorder that results in gradual wasting of the muscles of the hip and shoulder areas. Due to the inherent instability of calpain 3, recombinant expression of the full-length enzyme has not been possible, making in vitro analysis of specific LGMD2A-causing mutations difficult. However, because calpain 3 is highly similar in amino acid sequence to calpain 2, the recently solved crystal structure of full-length, Ca2+-bound, calpastatin-inhibited rat calpain 2 has allowed us to model calpain 3 as a Ca2+-bound homodimer. The model revealed three distinct areas of the enzyme that undergo a large conformational change upon Ca2+ binding. Located in these areas are several residues that undergo mutation to cause LGMD2A. We investigated the in vitro effects of six of these mutations by making the corresponding mutations in rat calpain 2. All six mutations examined in this study r...

  • functional defects of a muscle specific calpain p94 caused by mutations associated with limb girdle Muscular Dystrophy type 2a
    Journal of Biological Chemistry, 1998
    Co-Authors: Yasuko Ono, Jacques S. Beckmann, Hiroko Shimada, Hiroyuki Sorimachi, I Richard, Takaomi C Saido, Shoichi Ishiura, Koichi Suzuki
    Abstract:

    p94 (calpain3), a muscle-specific member of the calpain family, has been shown to be responsible for Limb-Girdle Muscular Dystrophy type 2A (LGMD2A), a form of autosomal recessive and progressive neuroMuscular disorder. To elucidate the molecular mechanism of LGMD2A, we constructed nine p94 missense point mutants found in LGMD2A and analyzed their p94 unique properties. All mutants completely or almost completely lose the proteolytic activity against a potential substrate, fodrin. However, some of the mutants still possess autolytic activity and/or connectin/titin binding ability, indicating these properties are not necessary for the LGMD2A phenotypes. These results provide strong evidence that LGMD2A results from the loss of proteolysis of substrates by p94, suggesting a novel molecular mechanism leading to Muscular dystrophies.

  • Characterization of Monoclonal Antibodies to Calpain 3 and Protein Expression in Muscle from Patients with Limb-Girdle Muscular Dystrophy Type 2A
    The American journal of pathology, 1998
    Co-Authors: Louise V. B. Anderson, Isabelle Richard, Keith Davison, Jennifer A. Moss, Michel Fardeau, Fernando M.s. Tomé, Christoph Hübner, Adriana Lasa, Jaume Colomer, Jacques S. Beckmann
    Abstract:

    Monoclonal antibodies were raised to two regions of calpain 3 (muscle-specific calcium-activated neutral protease), which is the product of the gene that is defective in Limb-Girdle Muscular Dystrophy type 2A. The antibodies produced characteristic patterns of bands on Western blots: normal calpain 3 protein was represented by bands at 94 kd, plus additional fragments at ∼60 or 30 kd, according to the antibody used. Specificity was confirmed by the loss of all bands in patients with null gene mutations. The “normal” profile of bands was observed in muscle from 33 control subjects and 70 disease-control patients. Calpain 3 protein was found to be extremely stable in fresh human muscle, with full-size protein being detected 8 hours after the muscle had been removed. Blots of muscle from nine Limb-Girdle Muscular Dystrophy type 2A patients with defined mutations showed variation in protein expression, with seven showing a clear reduction in the abundance of protein detected. No simple relationship was found between the abundance and clinical severity. Two patients showed normal expression of the full-size 94 kd band accompanied by a clear reduction in the smaller fragments. This pattern was also observed in one patient with an undefined form of Limb-Girdle Dystrophy. These results indicate that immunodiagnosis is feasible, but caution will need to be exercised with the interpretation of near-normal protein profiles.

  • chromosome 15 linked limb girdle Muscular Dystrophy clinical phenotypes in reunion island and french metropolitan communities
    Neuromuscular Disorders, 1996
    Co-Authors: Michel Fardeau, Isabelle Richard, B Eymard, C Mignard, F M S Tome, Jacques S. Beckmann
    Abstract:

    Erb's type Limb-Girdle Muscular Dystrophy (LGMD) was identified and clinically studied in detail in a small community living in the Reunion Island (RI). It was linked to chromosome 15q and related to mutations in the muscle specific calpain 3 gene. A series of cases were afterwards clinically and genetically identified in the French metropolitan community. The phenotype was identical to the RI type in the great majority of cases, although clinical differences were noticed in a few cases. Six different mutations were identified in the RI families, whereas a series of 39 mutations were detected in the French metropolitan families, all different from those present in the RI patients. Phenotype-genotype correlations were attempted in both communities.

  • confirmation of genetic heterogeneity in limb girdle Muscular Dystrophy linkage of an autosomal dominant form to chromosome 5q
    American Journal of Human Genetics, 1992
    Co-Authors: Marcy C Speer, L H Yamaoka, James H Gilchrist, C P Gaskell, Jeffrey M Stajich, Jeffery M Vance, Alexey Kazantsev, Anselmo A Lastra, Carol Haynes, Jacques S. Beckmann
    Abstract:

    Abstract Limb-Girdle Muscular Dystrophy (LGMD) is a clinically and genetically heterogeneous group of disorders, with both recessive and dominant forms reported. Recently, a series of recessive LGMD families were linked to chromosome 15q. We report herein the results of our linkage studies in a previously reported large autosomal dominant family. The LGMD gene in this family was localized to chromosome 5q22.3-31.3 by using a series of CA(n) microsatellite repeat markers. Linkage to 15q was excluded. These findings confirm genetic heterogeneity in this clinically diverse syndrome.

Kathryn R Wagner - One of the best experts on this subject based on the ideXlab platform.

  • etiology of limb girdle Muscular Dystrophy 1d 1e determined by laser capture microdissection proteomics
    Annals of Neurology, 2012
    Co-Authors: Steven A Greenberg, Mohammad Salajegheh, Daniel P Judge, Matthew W Feldman, Ralph W Kuncl, Zachary Waldon, Hanno Steen, Kathryn R Wagner
    Abstract:

    Limb girdle Muscular Dystrophy 1D/1E (OMIM nomenclature LGMD1D, Human Gene Nomenclature Committee LGMD1E), a skeletal and cardiac myopathy, has previously been linked to chromosome 6q23. We used laser capture microdissection to isolate cytoplasmic inclusions from skeletal muscle from a patient with LGMD1D/1E, performed mass spectrometry-based proteomics on these minute inclusions, and identified through bioinformatics desmin as their major constituent. Sequencing in this patient and family members identified the genetic basis of the previously reported 6q23 linked LGMD1D/1E to be due to an intron splice donor site mutation (IVS3+3A>G) of the desmin gene located on chromosome 2q35.

  • etiology of limb girdle Muscular Dystrophy 1d 1e determined by laser capture microdissection proteomics
    Annals of Neurology, 2012
    Co-Authors: Steven A Greenberg, Mohammad Salajegheh, Daniel P Judge, Matthew W Feldman, Ralph W Kuncl, Zachary Waldon, Hanno Steen, Kathryn R Wagner
    Abstract:

    Limb girdle Muscular Dystrophy 1D/1E (OMIM nomenclature LGMD1D, Human Gene Nomenclature Committee LGMD1E), a skeletal and cardiac myopathy, has previously been linked to chromosome 6q23. We used laser capture microdissection to isolate cytoplasmic inclusions from skeletal muscle from a patient with LGMD1D/1E, performed mass spectrometry–based proteomics on these minute inclusions, and identified through bioinformatics desmin as their major constituent. Sequencing in this patient and family members identified the genetic basis of the previously reported 6q23 linked LGMD1D/1E to be due to an intron splice donor site mutation (IVS3+3A>G) of the desmin gene located on chromosome 2q35. Ann Neurol 2011

Koichi Suzuki - One of the best experts on this subject based on the ideXlab platform.

  • skeletal muscle specific calpain p94 and connectin titin their physiological functions and relationship to limb girdle Muscular Dystrophy type 2a
    Advances in Experimental Medicine and Biology, 2000
    Co-Authors: Hiroyuki Sorimachi, Yasuko Ono, Koichi Suzuki
    Abstract:

    The skeletal muscle-specific calpain homologue, p94 (also called calpain 3), is essential for normal muscle function. A mutation of the p94 gene causes Limb-Girdle Muscular Dystrophy type 2A (LGMD2A), which is one type of autosomal recessive inherited disease characterized by progressive Muscular degeneration. In myofibrils, p94 specifically binds to connectin/ titin, and the activity of p94 is probably suppressed by this binding. Thus, we postulate that a signal transduction pathway exists, involving p94 and connectin/titin to modulate functions of skeletal muscle, and LGMD2A occurs when this signalling pathway is not properly regulated by p94. LGMD2A mutants of p94 also reveal significant information on the factors that relate structure to function in this molecule.

  • functional defects of a muscle specific calpain p94 caused by mutations associated with limb girdle Muscular Dystrophy type 2a
    Journal of Biological Chemistry, 1998
    Co-Authors: Yasuko Ono, Jacques S. Beckmann, Hiroko Shimada, Hiroyuki Sorimachi, I Richard, Takaomi C Saido, Shoichi Ishiura, Koichi Suzuki
    Abstract:

    p94 (calpain3), a muscle-specific member of the calpain family, has been shown to be responsible for Limb-Girdle Muscular Dystrophy type 2A (LGMD2A), a form of autosomal recessive and progressive neuroMuscular disorder. To elucidate the molecular mechanism of LGMD2A, we constructed nine p94 missense point mutants found in LGMD2A and analyzed their p94 unique properties. All mutants completely or almost completely lose the proteolytic activity against a potential substrate, fodrin. However, some of the mutants still possess autolytic activity and/or connectin/titin binding ability, indicating these properties are not necessary for the LGMD2A phenotypes. These results provide strong evidence that LGMD2A results from the loss of proteolysis of substrates by p94, suggesting a novel molecular mechanism leading to Muscular dystrophies.

Steven A. Moore - One of the best experts on this subject based on the ideXlab platform.

  • cardiac pathology exceeds skeletal muscle pathology in two cases of limb girdle Muscular Dystrophy type 2i
    Muscle & Nerve, 2009
    Co-Authors: Marta Margeta, Anne M. Connolly, Thomas L. Winder, Alan Pestronk, Steven A. Moore
    Abstract:

    Limb-Girdle Muscular Dystrophy type 2I (LGMD-2I) is caused by mutations in the fukutin-related protein gene (FKRP) that lead to abnormal glycosylation of alpha-dystroglycan in skeletal muscle. Heart involvement in LGMD-2I is common, but little is known about a underlying cardiac pathology. Herein we describe two patients with LGMD-2I (homozygous FKRP mutation c.826C>A, p.Leu276Ile) who developed severe congestive heart failure that required cardiac transplantation. The dystrophic pathology and impairment of alpha-dystroglycan glycosylation were severe in the heart but mild in skeletal muscle, underscoring the lack of correlation between cardiac and skeletal muscle involvement in some LGMD-2I patients.

  • Further evidence of Fukutin mutations as a cause of childhood onset Limb-Girdle Muscular Dystrophy without mental retardation
    Neuromuscular Disorders, 2009
    Co-Authors: R.l. Puckett, Thomas L. Winder, Steven A. Moore, Kevin P Campbell, Tobias Willer, Stephen G. Romansky, Kelly K. Covault, Jose E. Abdenur
    Abstract:

    The dystroglycanopathies comprise a clinically and genetically heterogeneous group of Muscular dystrophies characterized by deficient glycosylation of α-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital Muscular Dystrophy (FCMD), a severe form of dystroglycanopathy characterized by CMD, cobblestone lissencephaly and ocular defects. We describe two brothers of Caucasian and Japanese ancestry with normal intelligence and Limb-Girdle Muscular Dystrophy (LGMD) due to compound heterozygous FKTN mutations. Muscle biopsy showed a Dystrophy with selectively reduced α-dystroglycan glycoepitope immunostaining. Immunoblots revealed hypoglycosylation of α-dystroglycan and loss of laminin binding. FKTN gene sequencing identified two variants: c.340G>A and c.527T>C, predicting missense mutations p.A114T and p.F176S, respectively. Our results provide further evidence for ethnic and allelic heterogeneity and the presence of milder phenotypes in FKTN-dystroglycanopathy despite a substantial degree of α-dystroglycan hypoglycosylation in skeletal muscle.

  • Limb-Girdle Muscular Dystrophy in the United States.
    Journal of neuropathology and experimental neurology, 2006
    Co-Authors: Steven A. Moore, Christopher Shilling, Steven Westra, Cheryl Wall, Matthew Wicklund, Catherine A. Stolle, Charlotte A. Brown, Daniel E. Michele, F. Piccolo, Thomas L. Winder
    Abstract:

    Limb-Girdle Muscular Dystrophy (LGMD) has been linked to 15 chromosomal loci, 7 autosomal-dominant (LGMD1A to E) and 10 autosomal-recessive (LGMD2A to J). To determine the distribution of subtypes among patients in the United States, 6 medical centers evaluated patients with a referral diagnosis of LGMD. Muscle biopsies provided histopathology and immunodiagnostic testing, and their protein abnormalities along with clinical parameters directed mutation screening. The diagnosis in 23 patients was a disorder other than LGMD. Of the remaining 289 unrelated patients, 266 had muscle biopsies sufficient for complete microscopic evaluation; 121 also underwent Western blotting. From this combined evaluation, the distribution of immunophenotypes is 12% calpainopathy, 18% dysferlinopathy, 15% sarcoglycanopathy, 15% dystroglycanopathy, and 1.5% caveolinopathy. Genotypes distributed among 2 dominant and 7 recessive subtypes have been determined for 83 patients. This study of a large racially and ethnically diverse population of patients with LGMD indicates that establishing a putative subtype is possible more than half the time using available diagnostic testing. An efficient approach to genotypic diagnosis is muscle biopsy immunophenotyping followed by directed mutational analysis. The most common LGMDs in the United States are calpainopathies, dysferlinopathies, sarcoglycanopathies, and dystroglycanopathies.

  • Disruption of the β-Sarcoglycan Gene Reveals Pathogenetic Complexity of Limb-Girdle Muscular Dystrophy Type 2E
    Molecular cell, 2000
    Co-Authors: Ronald D. Cohn, Steven A. Moore, Ron F. Hrstka, Valérie Allamand, Beverly L. Davidson, Roger A. Williamson
    Abstract:

    Abstract Limb-Girdle Muscular Dystrophy type 2E (LGMD 2E) is caused by mutations in the β-sarcoglycan gene, which is expressed in skeletal, cardiac, and smooth muscle. β-sarcoglycan-deficient ( Sgcb -null) mice developed severe Muscular Dystrophy and cardiomyopathy with focal areas of necrosis. The sarcoglycan–sarcospan and dystroglycan complexes were disrupted in skeletal, cardiac, and smooth muscle membranes. e-sarcoglycan was also reduced in membrane preparations of striated and smooth muscle. Loss of the sarcoglycan–sarcospan complex in vascular smooth muscle resulted in vascular irregularities in heart, diaphragm, and kidneys. Further biochemical characterization suggested the presence of a distinct e-sarcoglycan complex in skeletal muscle that was disrupted in Sgcb -null mice. Thus, perturbation of vascular function together with disruption of the e-sarcoglycan-containing complex represents a novel mechanism in the pathogenesis of LGMD 2E.

Steven A Greenberg - One of the best experts on this subject based on the ideXlab platform.

  • etiology of limb girdle Muscular Dystrophy 1d 1e determined by laser capture microdissection proteomics
    Annals of Neurology, 2012
    Co-Authors: Steven A Greenberg, Mohammad Salajegheh, Daniel P Judge, Matthew W Feldman, Ralph W Kuncl, Zachary Waldon, Hanno Steen, Kathryn R Wagner
    Abstract:

    Limb girdle Muscular Dystrophy 1D/1E (OMIM nomenclature LGMD1D, Human Gene Nomenclature Committee LGMD1E), a skeletal and cardiac myopathy, has previously been linked to chromosome 6q23. We used laser capture microdissection to isolate cytoplasmic inclusions from skeletal muscle from a patient with LGMD1D/1E, performed mass spectrometry-based proteomics on these minute inclusions, and identified through bioinformatics desmin as their major constituent. Sequencing in this patient and family members identified the genetic basis of the previously reported 6q23 linked LGMD1D/1E to be due to an intron splice donor site mutation (IVS3+3A>G) of the desmin gene located on chromosome 2q35.

  • etiology of limb girdle Muscular Dystrophy 1d 1e determined by laser capture microdissection proteomics
    Annals of Neurology, 2012
    Co-Authors: Steven A Greenberg, Mohammad Salajegheh, Daniel P Judge, Matthew W Feldman, Ralph W Kuncl, Zachary Waldon, Hanno Steen, Kathryn R Wagner
    Abstract:

    Limb girdle Muscular Dystrophy 1D/1E (OMIM nomenclature LGMD1D, Human Gene Nomenclature Committee LGMD1E), a skeletal and cardiac myopathy, has previously been linked to chromosome 6q23. We used laser capture microdissection to isolate cytoplasmic inclusions from skeletal muscle from a patient with LGMD1D/1E, performed mass spectrometry–based proteomics on these minute inclusions, and identified through bioinformatics desmin as their major constituent. Sequencing in this patient and family members identified the genetic basis of the previously reported 6q23 linked LGMD1D/1E to be due to an intron splice donor site mutation (IVS3+3A>G) of the desmin gene located on chromosome 2q35. Ann Neurol 2011