title: RETRACTED: Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy.
abstract: No treatment is available for patients affected by the recessively inherited, progressive muscular dystrophies caused by a deficiency in the muscle membrane repair protein dysferlin. A marked reduction in dysferlin in patients harboring missense mutations in at least one of the two pathogenic DYSF alleles encoding dysferlin implies that dysferlin is degraded by the cell's quality control machinery. In vitro evidence suggests that missense mutated dysferlin might be functional if salvaged from degradation by the proteasome. We treated three patients with muscular dystrophy due to a homozygous Arg555Trp mutation in dysferlin with the proteasome inhibitor bortezomib and monitored dysferlin expression in monocytes and in skeletal muscle by repeated percutaneous muscle biopsy. Expression of missense mutated dysferlin in the skeletal muscle and monocytes of the three patients increased markedly, and dysferlin was correctly localized to the sarcolemma of muscle fibers on histological sections. Salvaged missense mutated dysferlin was functional in a membrane resealing assay in patient-derived muscle cells treated with three different proteasome inhibitors. We conclude that interference with the proteasomal system increases expression of missense mutated dysferlin, suggesting that this therapeutic strategy may benefit patients with dysferlinopathies and possibly other genetic diseases.
authors.affiliation: Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Bilal A
authors.initials: BA
authors.lastname: Azakir
authors.affiliation: Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Erne
authors.affiliation: Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Di Fulvio
authors.affiliation: Clinical Trial Unit, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Guido
authors.initials: G
authors.lastname: Stirnimann
authors.affiliation: Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospital Basel, 4031 Basel, Switzerland. michael.sinnreich@unibas.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Sinnreich
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000483:Alleles; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D000073939:Dysferlin; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics*; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001897:Boronic Acids; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib