Dysferlinopathies

Urtizberea, JAndoni; Bassez, Guillaume; Leturcq, F.; Nguyen, Karine; Krahn, Martin; Lévy, Nicolas

doi:10.4103/0028-3886.43447

Cited by 70 publications

(107 citation statements)

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“…6,7 Clinically, many patients are misdiagnosed as having an inflammatory myopathy, specifically polymyositis, due to the prominence of interstitial infiltration by macrophages. 12,13 However, unlike autoimmune myositis, the human leukocyte antigeneclass I complex is not overexpressed in dysferlinopathies. 14 Here we employ a previously validated in vivo muscleinjury model that uses repeated large-strain lengthening contractions of the hind limb ankle dorsiflexor muscles (largestrain injury; LSI) to investigate the contribution of inflammation to structural and functional damage in dysferlinopathic muscle following exercise-induced injury.…”

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confidence: 98%

Myofiber Damage Precedes Macrophage Infiltration after in Vivo Injury in Dysferlin-Deficient A/J Mouse Skeletal Muscle

Roche

Tulapurkar

Mueller

et al. 2015

The American Journal of Pathology

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Mutations in the dysferlin gene (DYSF) lead to human muscular dystrophies known as dysferlinopathies. The dysferlin-deficient A/J mouse develops a mild myopathy after 6 months of age, and when younger models the subclinical phase of the human disease. We subjected the tibialis anterior muscle of 3- to 4-month-old A/J mice to in vivo large-strain injury (LSI) from lengthening contractions and studied the progression of torque loss, myofiber damage, and inflammation afterward. We report that myofiber damage in A/J mice occurs before inflammatory cell infiltration. Peak edema and inflammation, monitored by magnetic resonance imaging and by immunofluorescence labeling of neutrophils and macrophages, respectively, develop 24 to 72 hours after LSI, well after the appearance of damaged myofibers. Cytokine profiles 72 hours after injury are consistent with extensive macrophage infiltration. Dysferlin-sufficient A/WySnJ mice show much less myofiber damage and inflammation and lesser cytokine levels after LSI than do A/J mice. Partial suppression of macrophage infiltration by systemic administration of clodronate-incorporated liposomes fails to suppress LSI-induced damage or to accelerate torque recovery in A/J mice. The findings from our studies suggest that, although macrophage infiltration is prominent in dysferlin-deficient A/J muscle after LSI, it is the consequence and not the cause of progressive myofiber damage.

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confidence: 98%

Myofiber Damage Precedes Macrophage Infiltration after in Vivo Injury in Dysferlin-Deficient A/J Mouse Skeletal Muscle

Roche

Tulapurkar

Mueller

et al. 2015

The American Journal of Pathology

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“…The main clinical presentations are the distal-onset muscular dystrophy called ,Miyoshi myopathy and the proximal-onset form LGMD2B, both characterized by progressive muscle weakness, usually appearing in the second decade, and highly elevated serum creatine kinase (CK) levels. Progressively, the description of different phenotypes caused by DYSF mutations Klinge, et al, 2008;Nguyen, et al, 2005;Nguyen, et al, 2007;Okahashi, et al, 2008;Paradas, et al, 2009;Seror, et al, 2008;Spuler, et al, 2008;Ueyama, et al, 2002;Wenzel, et al, 2007), in addition to the "typical" LGMD and Miyoshi phenotypes, unraveled a wide spectrum of phenotypes, ranging from clinically asymptomatic, isolated hyperCKemia to severe and early onset presentations (Bushby, 2000;Laval and Bushby, 2004;Urtizberea, et al, 2008). This wide range of clinical presentations is collectively referred to as dysferlinopathies.…”

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confidence: 99%

UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene

et al. 2011

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Mutations in the dysferlin gene (DYSF) lead to a complete or partial absence of the dysferlin protein in skeletal muscles and are at the origin of dysferlinopathies, a heterogeneous group of rare autosomal recessive inherited neuromuscular disorders. As a step towards a better understanding of the DYSF mutational spectrum, and towards possible inclusion of patients in future therapeutic clinical trials, we set up the Universal Mutation Database for Dysferlin (UMD-DYSF), a Locus-Specific Database developed with the UMD® software. The main objective of UMD-DYSF is to provide an updated compilation of mutational data and relevant interactive tools for the analysis of DYSF sequence variants, for diagnostic and research purposes. In particular, specific algorithms can facilitate the interpretation of newly identified intronic, missense-or isosemantic-exonic sequence variants, a problem encountered recurrently during genetic diagnosis in dysferlinopathies. UMD-DYSF v1.0 is freely accessible at www.umd.be/DYSF/. It contains a total of 742 mutational entries corresponding to 266 different disease-causing mutations identified in 558 patients worldwide diagnosed with dysferlinopathy. This article presents for the first time a comprehensive analysis of the dysferlin mutational spectrum based on all compiled DYSF diseasecausing mutations reported in the literature to date, and using the main bioinformatics tools offered in UMD-DYSF.

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“…The DYSF gene encodes dysferlin, a 230-kDa protein that is absent or severely reduced in patients with limb girdle muscular dystrophy type 2B, Miyoshi myopathy, and distal myopathy with anterior tibial onset, skeletal muscle-wasting syndromes collectively referred to as dysferlinopathies (Urtizberea et al 2008). Inheritance is autosomal recessive, and disease-causing mutations have been identified across the DYSF gene (Nguyen et al 2005).…”

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confidence: 99%

Unmasking Potential Intracellular Roles For Dysferlin through Improved Immunolabeling Methods

Roche

O’Neill

et al. 2011

J Histochem Cytochem.

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Mutations in the DYSF gene that severely reduce the levels of the protein dysferlin are implicated in muscle-wasting syndromes known as dysferlinopathies. Although studies of its function in skeletal muscle have focused on its potential role in repairing the plasma membrane, dysferlin has also been found, albeit inconsistently, in the sarcoplasm of muscle fibers. The aim of this article is to study the localization of dysferlin in skeletal muscle through optimized immunolabeling methods. We studied the localization of dysferlin in control rat skeletal muscle using several different methods of tissue collection and subsequent immunolabeling. We then applied our optimized immunolabeling methods on human cadaveric muscle, control and dystrophic human muscle biopsies, and control and dysferlin-deficient mouse muscle. Our data suggest that dysferlin is present in a reticulum of the sarcoplasm, similar but not identical to those containing the dihydropyridine receptors and distinct from the distribution of the sarcolemmal protein dystrophin. Our data illustrate the importance of tissue fixation and antigen unmasking for proper immunolocalization of dysferlin. They suggest that dysferlin has an important function in the internal membrane systems of skeletal muscle, involved in calcium homeostasis and excitation-contraction coupling.

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Dysferlinopathies

Cited by 70 publications

References 0 publications

Myofiber Damage Precedes Macrophage Infiltration after in Vivo Injury in Dysferlin-Deficient A/J Mouse Skeletal Muscle

Myofiber Damage Precedes Macrophage Infiltration after in Vivo Injury in Dysferlin-Deficient A/J Mouse Skeletal Muscle

UMD-DYSF, a novel locus specific database for the compilation and interactive analysis of mutations in the dysferlin gene

Unmasking Potential Intracellular Roles For Dysferlin through Improved Immunolabeling Methods

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