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

Blandin, Gaëlle; Béroud, Christophe; Labelle, Véronique; Nguyen, Karine; Wein, Nicolas; Hamroun, Dalil; Williams, Brad J.; Monnier, Nilah; Rufibach, Laura; Urtizberea, Jon Andoni; Cau, Pierre; Bartoli, Marc; Lévy, Nicolas; Krahn, Martin

doi:10.1002/humu.22015

Cited by 38 publications

(55 citation statements)

References 61 publications

(72 reference statements)

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“…Missense mutations, which represent 33.1% of mutations in DYSF [Blandin et al, 2012], could perturb splicing. Indeed, modifications of the sequence of the protein could lead to a wrong localization of the protein or perturb interactions with partners; nevertheless, these proteins could be produced and stable.…”

Section: Discussionmentioning

confidence: 99%

“…We used the UMD-predictor algorithm [Frédéric et al, 2009], available through the online UMD-DYSF database [Blandin et al, 2012], to predict the deleterious effect of missense mutations.…”

Section: Predictions Of the Pathogenicity Of Mutationsmentioning

confidence: 99%

“…Mutational analysis of DYSF is confronted to a wide mutational spectrum, and associated interpretational difficulties for novel DYSF sequence variants, in particular putative splicing and missense variants. In a comprehensive analysis of the dysferlin mutational spectrum, using the locus-specific database UMD-DYSF (www.umd.be/DYSF/), we recently characterized the DYSF mutational spectrum based on all compiled DYSF disease-causing mutations reported in the literature [Blandin et al, 2012]. Among 266 different disease-causing mutations (from a total of 742 mutational entries corresponding to variations identified in 558 patients worldwide), 33.1% corresponded to missense mutations and 17.3% to intronic mutations.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Splicing Defects Caused by Mutations in the Dysferlin Gene

et al. 2014

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Missense, iso-semantic, and intronic mutations are challenging for interpretation, in particular for their impact in mRNA. Various tools such as the Human Splicing Finder (HSF) system could be used to predict the impact on splicing; however, no diagnosis result could rely on predictions alone, but requires functional testing. Here, we report an in vitro approach to study the impact of DYSF mutations on splicing. It was evaluated on a series of 45 DYSF mutations, both intronic and exonic. We confirmed splicing alterations for all intronic mutations localized in 5 or 3 splice sites. Then, we showed that DYSF missense mutations could also result in splicing defects: mutations c.463G>A and c.2641A>C abolished ESEs and led to exon skipping; mutations c.565C>G and c.1555G>A disrupted Exonic Splicing Enhancer (ESE), while concomitantly creating new 5 or 3 splice site leading to exonic out of frame deletions. We demonstrated that 20% of DYSF missense mutations have a strong impact on splicing. This minigene strategy is an efficient tool for the detection of splicing defects in dysferlinopathies, which could allow for a better comprehension of splicing defects due to mutations and could improve prediction tools evaluating splicing defects.

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Section: Discussionmentioning

confidence: 99%

Section: Predictions Of the Pathogenicity Of Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Splicing Defects Caused by Mutations in the Dysferlin Gene

et al. 2014

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“…[2,3] Dysferlinopathies have been reported in different populations, [4] including 15 Chinese patients with genetic studies. [5][6][7] We report mutational data from the largest Chinese cohort to date, including 31 novel disease-causing mutations which point to a specific mutational spectrum.…”

Section: Introductionmentioning

confidence: 99%

Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy

Blandin

et al. 2014

Neurol India

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“…There are 14 isoforms of DYSF that arise from use of two separate promoters and alternate exon splicing, with isoform 8 being predominant in skeletal muscle 23. Disease-causing mutations in DYSF occur throughout the gene with no obvious hot spots or correlations with specific disease features 24. Genetic data compiled in Universal Mutation Database for Dysferlin (UMD-DYSF, v.1.1 26 April 2013, http://www.umd.be/DYSF/)24 list 337 disease-causing mutations that have been found in 725 patients worldwide.…”

Section: Introductionmentioning

confidence: 99%

A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides

Dominov

Uyan

Sapp

et al. 2014

Ann Clin Transl Neurol

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ObjectiveMutations in dysferlin (DYSF), a Ca2+-sensitive ferlin family protein important for membrane repair, vesicle trafficking, and T-tubule function, cause Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal myopathy. More than 330 pathogenic DYSF mutations have been identified within exons or near exon–intron junctions. In ~17% of patients who lack normal DYSF, only a single disease-causing mutation has been identified. We studied one family with one known mutant allele to identify both the second underlying genetic defect and potential therapeutic approaches.MethodsWe sequenced the full DYSF cDNA and investigated antisense oligonucleotides (AONs) as a tool to modify splicing of the mRNA transcripts in order to process out mutant sequences.ResultsWe identified a novel pseudoexon between exons 44 and 45, (pseudoexon 44.1, PE44.1), which inserts an additional 177 nucleotides into the mRNA and 59 amino acids within the conserved C2F domain of the DYSF protein. Two unrelated dysferlinopathy patients were also found to carry this mutation. Using AONs targeting PE44.1, we blocked the abnormal splicing event, yielding normal, full-length DYSF mRNA, and increased DYSF protein expression.InterpretationThis is the first report of a deep intronic mutation in DYSF that alters mRNA splicing to include a mutant peptide fragment within a key DYSF domain. We report that AON-mediated exon-skipping restores production of normal, full-length DYSF in patients’ cells in vitro, offering hope that this approach will be therapeutic in this genetic context, and providing a foundation for AON therapeutics targeting other pathogenic DYSF alleles.

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

Cited by 38 publications

References 61 publications

Identification of Splicing Defects Caused by Mutations in the Dysferlin Gene

Identification of Splicing Defects Caused by Mutations in the Dysferlin Gene

Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy

A novel dysferlin mutant pseudoexon bypassed with antisense oligonucleotides

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