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

  • Nat Commun. 2019 Mar 27;10(1):1396. doi: 10.1038/s41467-019-09111-2.
Montse Olivé  1 ,  Martin Engvall  2  3 ,  Gianina Ravenscroft  4 ,  Macarena Cabrera-Serrano  5 ,  Hong Jiao  6  7 ,  Carlo Augusto Bortolotti  8 ,  Marcello Pignataro  9 ,  Matteo Lambrughi  8 ,  Haibo Jiang  10 ,  Alistair R R Forrest  4 ,  Núria Benseny-Cases  11 ,  Stefan Hofbauer  12 ,  Christian Obinger  12 ,  Gianantonio Battistuzzi  9 ,  Marzia Bellei  8 ,  Marco Borsari  9 ,  Giulia Di Rocco  8 ,  Helena M Viola  13 ,  Livia C Hool  13  14 ,  Josep Cladera  15 ,  Kristina Lagerstedt-Robinson  16 ,  Fengqing Xiang  17 ,  Anna Wredenberg  3  18 ,  Francesc Miralles  19 ,  Juan José Baiges  20 ,  Edoardo Malfatti  21  22 ,  Norma B Romero  21  22 ,  Nathalie Streichenberger  23 ,  Christophe Vial  24 ,  Kristl G Claeys  25  26 ,  Chiara S M Straathof  27 ,  An Goris  28 ,  Christoph Freyer  3  18 ,  Martin Lammens  29  30  31 ,  Guillaume Bassez  32 ,  Juha Kere  6  7  33  34 ,  Paula Clemente  18 ,  Thomas Sejersen  17 ,  Bjarne Udd  35  36  37 ,  Noemí Vidal  38 ,  Isidre Ferrer  38  39 ,  Lars Edström  40 ,  Anna Wedell  2  3 ,  Nigel G Laing  41
Affiliations
  • 1. Neuropathology Unit, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, 08907, Spain. [email protected].
  • 2. Department of Molecular Medicine and Surgery, Science for Life Laboratory, Karolinska Institutet, Stockholm, SE-17176, Sweden.
  • 3. Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, SE-17177, Sweden.
  • 4. Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, Perth, 6000, WA, Australia.
  • 5. Neurology Department and Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Seville, 41013, Spain.
  • 6. Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, Stockholm, SE-14157, Sweden.
  • 7. Clinical Research Centre, Karolinska University Hospital, Huddinge, SE-17177, Sweden.
  • 8. Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 41121, Italy.
  • 9. Department of Chemical and Geological Sciences, University of Modena and Reggio Emilia, Modena, 41121, Italy.
  • 10. School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, 6009, WA, Australia.
  • 11. ALBA Synchrotron Light Source, Cerdanyola del Vallès, Barcelona, 08290, Spain.
  • 12. Division of Biochemistry, Department of Chemistry, Vienna Institute of BioTechnology, BOKU-University of Natural Resources and Life Sciences, Vienna, A-1180, Austria.
  • 13. School of Human Sciences, The University of Western Australia, Perth, 6000, Western Australia, Australia.
  • 14. Victor Chang Cardiac Research Institute, Darlinghurst, 2010, NSW, Australia.
  • 15. Unitat de Biofísica, Departament de Bioquímica i de Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain.
  • 16. Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, Solna, Stockholm, SE-17176, Sweden.
  • 17. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SE-17177, Sweden.
  • 18. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SE-17177, Sweden.
  • 19. Neurology Department, Hospital Son Espases, Palma de Mallorca, 07120, Spain.
  • 20. Neurology Department, Hospital Verge de la Cinta, Tortosa, 43500, Spain.
  • 21. Université Sorbonne, UPMC Univ Paris 06, INSERM; UMRS974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, 47 Boulevard de l'hôpital, 75013, Paris, France.
  • 22. Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, 75013, France.
  • 23. Centre de Pathologie et Neuropathologie Est, Hospices Civils de Lyon; Université Claude Bernard Lyon1, Institut NeuroMyogène CNRS UMR 5310-INSERM U1217; Institut NeuroMyogène, Villeurbanne, 69677, France.
  • 24. Electromyographie-Groupement Hospitalier Est, Hospices Civils de Lyon, 69677, France.
  • 25. Department of Neurology, University Hospitals Leuven, Leuven, 2333, Belgium.
  • 26. KU Leuven-University of Leuven, Laboratory for Muscle diseases and Neuropathies, Department of Neurosciences, Experimental Neurology, Leuven, 2333, Belgium.
  • 27. Department of Neurology, Leiden University Medical Center, Leiden, 2333, The Netherlands.
  • 28. KU Leuven-University of Leuven, Laboratory for Neuroimmunology, Department of Neurosciences, Experimental Neurology, Leuven, 2333, Belgium.
  • 29. Department of Pathology, Antwerp University Hospital, Edegem, 2650, Belgium.
  • 30. Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Wilrijk, 2610, Belgium.
  • 31. Department of Pathology, Radboud University Medical Center, Nijmegen, 6525, The Netherlands.
  • 32. Neuromuscular Reference Center, Henri Mondor University Hospital AP-HP, INSERM U955, Team 10, Biology of the Neuromuscular System, East-Paris University (UPEC), Paris, 94010, France.
  • 33. Molecular Neurology Research Program, University of Helsinki and Folkhälsan Institute of Genetics, Helsinki, 00014, Finland.
  • 34. School of Basic and Medical Biosciences, King's College London, London, WC2R2LS, UK.
  • 35. Neuromuscular Research Center, Tampere University Hospital, University of Tampere, Tampere, 33521, Finland.
  • 36. Folkhälsan Genetic Institute, University of Helsinki, Helsinki, 00250, Finland.
  • 37. Neurology Department, Vasa Central Hospital, Vasa, Finland Neuromuscular Research Center, Tampere University Hospital, University of Tampere, Tampere, 65100, Finland.
  • 38. Neuropathology Unit, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, 08907, Spain.
  • 39. Department of Pathology and Experimental Therapeutics, University of Barcelona, CIBERNEDHospitalet de LLobregat, Barcelona, 08907, Spain.
  • 40. Center for Molecular Medicine, Karolinska Institutet, Stockolm, 17177, Sweden.
  • 41. Centre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, Perth, 6000, WA, Australia. [email protected].
PMID: 30918256 DOI: 10.1038/s41467-019-09111-2
Abstract

Myoglobin, encoded by MB, is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O2, 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 O2 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.