Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy

Akiyama, Masashi; Liu, J.; Richard, Isabelle; Bashir, Rumaisa; Britton, Steve L.; Keers, Sharon; Oeltjen, Joshua; Brown, Heidi E.; Marchand, Sylvie; Bourg, Nathalie; Beley, Cyriaque; McKenna‐Yasek, Diane; Arahata, Kiichi; Bohlega, Saeed; Cupler, Edward; Illa, Isabel; Majneh, I.; Barohn, Richard J.; Urtizberea, J.A.; Fardeau, Michel; Amato, Anthony A.; Angelini, C.; Bushby, Kate; Beckmann, Jacques S.; Brown, Robert H.

doi:10.1212/wnl.57.2.271

Cited by 126 publications

(116 citation statements)

References 29 publications

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“…Two mutations lie within the DysfNC domain, a nested repeat sequence in many ferlins and several other proteins, whose function is unknown. Missense mutations within this domain in dysferlin have been linked to Miyoshi myopathy (Aoki et al, 2001;Matsumura et al, 1999) also indicating its importance.…”

Section: +mentioning

confidence: 99%

FER-1 regulates Ca2+-mediated membrane fusion during C. elegans spermatogenesis

Washington

Ward

2006

Journal of Cell Science

129

148

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FER-1 is required for fusion of specialized vesicles, called membranous organelles, with the sperm plasma membrane during Caenorhabditis elegans spermiogenesis. To investigate its role in membranous organelle fusion, we examined ten fer-1 mutations and found that they all cause the same defect in membrane fusion. FER-1 and the ferlin protein family are membrane proteins with four to seven C2 domains. These domains commonly mediate Ca2+-dependent lipid-processing events. Most of the fer-1 mutations fall within these C2 domains, showing that they have distinct, non-redundant functions. We found that membranous organelle fusion requires intracellular Ca2+ and that C2 domain mutations alter Ca2+ sensitivity. This suggests that the C2 domains are involved in Ca2+ sensing and further supports their independent function. Using two immunological approaches we found three FER-1 isoforms, two of which might arise from FER-1 by proteolysis. By both light and electron microscopy, these FER-1 proteins were found to be localized to membranous organelle membranes. Dysferlin, a human homologue of FER-1 involved in muscular dystrophy, is required for vesicle fusion during Ca2+-induced muscle membrane repair. Our results suggest that the ferlin family members share a conserved mechanism to regulate cell-type-specific membrane fusion.

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Section: +mentioning

confidence: 99%

FER-1 regulates Ca2+-mediated membrane fusion during C. elegans spermatogenesis

Washington

Ward

2006

Journal of Cell Science

129

148

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“…DYSF1 contains amino-acid (aa) residues 2 -245 and has high homology with myoferlin and otoferlin, while DYSF2 contains residues 1666 -1788 and shows no homology to any known human protein. 18 To generate DYSF1, a 740 bp fragment was PCR amplified from human muscle cDNA with forward primer (5 0 -CGA GAT CTC TGA GGG TCT TCA TCC TCT ATG-3 0 ) and reverse primer (5 0 -CTC AAG CTT AGC GGT AAC CTT GAC CAC AGG-3 0 ) and cloned into the TOPO 2.1 vector (Invitrogen, Carlsbad, CA, USA). To generate DYSF2, a 375 bp fragment was similarly PCR amplified with forward primer (5 0 -GGA TCC CTG GAG AAC AGG CT-3 0 ) and reverse primer (5 0 -GTC GAC CCA CAT CTG CAG CT-3 0 ) and also cloned into TOPO 2.1.…”

Section: Recombinant Antigen Productionmentioning

confidence: 99%

“…All were previously studied by conventional Western blot analysis for suspected dysferlinopathy. For mutation screening, individual exons of dysferlin were amplified from genomic DNA with Immolase (Bioline, Randolph, MA, USA) as described, 18 with minor modification (primers sequences available on request). Amplified products included intron/exon boundaries and all protein coding sequences.…”

Section: Immunoprecipitationmentioning

confidence: 99%

Protein studies in dysferlinopathy patients using llama-derived antibody fragments selected by phage display

et al. 2005

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Mutations in dysferlin, a member of the fer1-like protein family that plays a role in membrane integrity and repair, can give rise to a spectrum of neuromuscular disorders with phenotypic variability including limbgirdle muscular dystrophy 2B, Myoshi myopathy and distal anterior compartment myopathy. To improve the tools available for understanding the pathogenesis of the dysferlinopathies, we have established a large source of highly specific antibody reagents against dysferlin by selection of heavy-chain antibody fragments originating from a nonimmune llama-derived phage-display library. By utilizing different truncated forms of recombinant dysferlin for selection and diverse selection methodologies, antibody fragments with specificity for two different dysferlin domains could be identified. The selected llama antibody fragments are functional in Western blotting, immunofluorescence microscopy and immunoprecipitation applications. Using these antibody fragments, we found that calpain 3, which shows a secondary reduction in the dysferlinopathies, interacts with dysferlin.

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“…In skeletal muscle, dysferlin participates in membrane wound repair mechanisms (Bansal et al, 2003), and these repair mechanisms are thought to involve membrane fusion (Bansal et al, 2003;Lennon et al, 2003). Mutations in the gene encoding dysferlin cause limb girdle muscular dystrophy-2B (LGMD2B) and Miyoshi muscular dystrophy (MMD) (Aoki et al, 2001;Bashir et al, 1994;Liu et al, 1998). At present, there are no treatments available for these muscle-wasting diseases.…”

Section: Introductionmentioning

confidence: 99%

Membrane wounding triggers ATP release and dysferlin-mediated intercellular calcium signaling

Covian-Nares

Koushik

Puhl

et al. 2010

Journal of Cell Science

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SummaryDysferlin is a Ca 2+ -binding protein found in many different cell types. It is required for membrane wound repair in muscle, but it is not known whether it has the same function in other cells. Here we report the activation of an intercellular signaling pathway in sea urchin embryos by membrane wounding that evokes Ca 2+ spikes in neighboring cells. This pathway was mimicked by ATP application, and inhibited by apyrase, cadmium, and -agatoxin-IVA. Microinjection of dysferlin antisense phosphorodiamidate morpholino oligonucleotides blocked this pathway, whereas control morpholinos did not. Co-injection of mRNA encoding human dysferlin with the inhibitory morpholino rescued signaling activity. We conclude that in sea urchin embryos dysferlin mediates Ca 2+ -triggered intercellular signaling in response to membrane wounding.

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Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy

Cited by 126 publications

References 29 publications

FER-1 regulates Ca2+-mediated membrane fusion during C. elegans spermatogenesis

FER-1 regulates Ca2+-mediated membrane fusion during C. elegans spermatogenesis

Protein studies in dysferlinopathy patients using llama-derived antibody fragments selected by phage display

Membrane wounding triggers ATP release and dysferlin-mediated intercellular calcium signaling

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