Journal Article

Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions

Miralles, Francesc, Engvall, Martin, Ravenscroft, Gianina, Wedell, Anna, Jiang, Haibo, Lambrughi, Matteo, Hool, Livia C., Edström, Lars, Bellei, Marzia, Xiang, Fengqing, Olivé, Montse, Cladera, Josep, Jiao, Hong, Straathof, Chiara S. M., Vial, Christophe, Forrest, Alistair R. R., Baiges, Juan José, Malfatti, Edoardo, Cabrera-Serrano, Macarena, Streichenberger, Nathalie, Ferrer, Isidre, Benseny-Cases, Núria, Borsari, Marco, Romero, Norma B., Kere, Juha, Udd, Bjarne, Battistuzzi, Gianantonio, Wredenberg, Anna, Lagerstedt-Robinson, Kristina, Obinger, Christian, Di Rocco, Giulia, Bassez, Guillaume, Lammens, Martin, Laing, Nigel G., Goris, An, Clemente, Paula, Claeys, Kristl G., Hofbauer, Stefan, Vidal, Noemí, Freyer, Christoph, Sejersen, Thomas, Bortolotti, Carlo Augusto, Viola, Helena M., Pignataro, Marcello

2019

Overview

Myoglobin, encoded by MB , is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O 2, facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T (p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O 2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation. Myoglobin is a hemeprotein that reversibly binds oxygen and gives muscle its red color. Here, the authors report a genetic variant in the MB gene that associates with myoglobinopathy, an autosomal dominant progressive myopathy, and altered oxygen binding properties of the mutant protein.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 14/28 / 38/23 / 42/41 / 631/208/1516 / 631/208/737 / 692/308 / 692/308/2056 / Adult / Biochemistry / Biochemistry, Molecular Biology / Biopsy / Cardiac muscle / Cardiomyocytes / Coding / Dysphagia / European Continental Ancestry Group - genetics / Female / Genetic variance / Heart Failure - etiology / Heme / Heme - metabolism / Human health and pathology / Humanities and Social Sciences / Humans / Inclusion Bodies - pathology / Inclusions / Life Sciences / Magnetic resonance imaging / Male / Middle Aged / multidisciplinary / Muscle Fibers, Skeletal - pathology / Muscle Weakness - genetics / Muscle Weakness - physiopathology / Muscle, Skeletal - diagnostic imaging / Muscle, Skeletal - physiopathology / Muscles / Muscular Diseases - diagnostic imaging / Muscular Diseases - genetics / Muscular Diseases - pathology / Muscular Diseases - physiopathology / Mutation / Myocytes / Myocytes, Cardiac - pathology / Myoglobin - genetics / Myoglobins / Myopathy / Nitric oxide / Oxygen / Oxygen - metabolism / Pedigree / Proteins / Reactive oxygen species / Respiratory Insufficiency - etiology / Science / Science (multidisciplinary) / Skeletal muscle / Superoxide / Superoxides - metabolism / Tomography, X-Ray Computed