Analysis of the<i>DYSF</i>mutational spectrum in a large cohort of patients

Krahn, Martin; Béroud, Christophe; Labelle, Véronique; Nguyen, Karine; Bernard, R.; Bassez, Guillaume; Figarella‐Branger, Dominique; Fernandez, Carla; Bouvenot, Julien; Richard, Isabelle; Ollagnon‐Roman, Elisabeth; Bevilacqua, Jorge A.; Salvo, Eric; Attarian, Shahram; Chapon, Françoise; Pellissier, Jean‐François; Pouget, Jean; Hammouda, El Hadi; Laforêt, Pascal; Urtizberea, Jon Andoni; Eymard, B.; Lévy, Nicolas

doi:10.1002/humu.20910

Cited by 105 publications

(107 citation statements)

References 16 publications

(33 reference statements)

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“…Importantly, the second DYSF allele in the 180/06 cells harbors a mis-sense mutation, exchanging arginine 555 for a tryptophan (R555W). This missense mutation has been described previously (11)(12)(13)(14) and represents the fourth most common mis-sense mutation in the dysferlin gene, according to the Leiden muscular dystrophy Web site. 180/06 myoblasts produce barely detectable amounts of dysferlin (Fig.…”

Section: Characterization Of Human Myoblast Cultures: Dysf Mutations mentioning

confidence: 42%

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Azakir

Fulvio

Kinter

et al. 2012

Journal of Biological Chemistry

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Background: Dysferlin encoded by mis-sense alleles is rapidly degraded in skeletal muscle. Results: Proteasomal inhibitors increase dysferlin levels, restore membrane repair and myotube formation in patient-derived myoblasts harboring mis-sense mutated dysferlin. Conclusion: Proteasomal inhibition restores function of mis-sense mutated dysferlin. Significance: Inhibiting the degradation of mis-sense mutated dysferlin may be a therapeutic strategy for dysferlinopathies with certain mis-sense mutations.

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Section: Characterization Of Human Myoblast Cultures: Dysf Mutations mentioning

confidence: 42%

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Azakir

Fulvio

Kinter

et al. 2012

Journal of Biological Chemistry

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“…Furthermore, interactive functions allow for analysis of the full UMD-DYSF dataset, single mutational events or customized subsets of mutations referenced in the database. We previously used an offline version of UMD-DYSF to successfully analyse the mutational spectrum of a large cohort of patients analysed for DYSF mutations in our diagnostic laboratory (Krahn, et al, 2009a). To further illustrate the use of UMD-DYSF, we here report the results of statistical analyses of the DYSF mutational spectrum based for the first time on all compiled DYSF disease-causing mutations reported in the literature to date.…”

Section: Introductionsupporting

confidence: 49%

“…The total number of patients amounts to 401 index cases (557 mutational entries) and 157 relatives. Among all UMD-DYSF entries, 192 entries from 129 patients correspond to mutations identified in our laboratory (Khadilkar, et al, 2008;Krahn, et al, 2009a;Krahn, et al, 2009b;Nguyen, et al, 2005;Nguyen, et al, 2007;Seror, et al, 2008) while the others correspond to mutational data reported in 55 additional publications (see www.umd.be/DYSF/ for a comprehensive list of references). All mutational data can be visualized through the "Search" function described in Table 1 and downloaded from the UMD-DYSF website.…”

Section: Database Entriessupporting

confidence: 42%

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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“…Loss of dysferlin is frequently associated with nonsense or frameshift mutations (7,66). However, except for rare cases (for example, exon 32 deletion causes mild dysferlinopathy [see below, 72]), no measurable phenotype to genotype correlation was established.…”

Section: What Are the Mutations Involved In Dysferlinopathies?supporting

confidence: 43%

“…Because the discovery that DYSF dysfunction underlies both LGMD2B (1) and MM (2), a wide spectrum of DYSF mutations has been identified, including missense, nonsense, frameshift deletions/ insertions, splicing mutations and large deletions (1,2,7,8,46,65,66). Although no mutational hotspots were identified (UMD-DYSF database, Leiden muscular dystrophy pages: http:// www.…”

Section: What Are the Mutations Involved In Dysferlinopathies?mentioning

confidence: 42%

Translational Research and Therapeutic Perspectives in Dysferlinopathies

Barthélémy

Wein

Krahn

et al. 2011

Mol Med

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Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene, encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) and the second most common being LGMD. Symptoms generally appear at the end of childhood and, although disease progression is typically slow, walking impairments eventually result. Dysferlin is a modular type II transmembrane protein for which numerous binding partners have been identified. Although dysferlin function is only partially elucidated, this large protein contains seven calcium sensor C2 domains, shown to play a key role in muscle membrane repair. On the basis of this major function, along with detailed clinical observations, it has been possible to design various therapeutic approaches for dysferlin-deficient patients. Among them, exon-skipping and minigene transfer strategies have been evaluated at the preclinical level and, to date, represent promising approaches for clinical trials. This review aims to summarize the pathophysiology of dysferlinopathies and to evaluate the therapeutic potential for treatments currently under development.

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Analysis of theDYSFmutational spectrum in a large cohort of patients

Cited by 105 publications

References 16 publications

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

Proteasomal Inhibition Restores Biological Function of Mis-sense Mutated Dysferlin in Patient-derived Muscle Cells

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

Translational Research and Therapeutic Perspectives in Dysferlinopathies

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