2. Academic Validation
  3. Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions

Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions

  • Acta Neuropathol. 2021 Aug;142(2):375-393. doi: 10.1007/s00401-021-02319-x.
Mridul Johari 1 2,  Jaakko Sarparanta 3 4,  Anna Vihola 3 4 5,  Per Harald Jonson 3 4,  Marco Savarese 3 4,  Manu Jokela 6 7,  Annalaura Torella 8,  Giulio Piluso 8,  Edith Said 9 10,  Norbert Vella 11,  Marija Cauchi 11,  Armelle Magot 12,  Francesca Magri 13,  Eleonora Mauri 13,  Cornelia Kornblum 14,  Jens Reimann 14,  Tanya Stojkovic 15,  Norma B Romero 16,  Helena Luque 3 4,  Sanna Huovinen 17,  Päivi Lahermo 18,  Kati Donner 18,  Giacomo Pietro Comi 19 20,  Vincenzo Nigro 8 21,  Peter Hackman 3 4,  Bjarne Udd 3 4 6 22
Affiliations

Affiliations

  • 1 Folkhälsan Research Center, Helsinki, Finland. [email protected].
  • 2 Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland. [email protected].
  • 3 Folkhälsan Research Center, Helsinki, Finland.
  • 4 Department of Medical Genetics, Medicum, University of Helsinki, Helsinki, Finland.
  • 5 Neuromuscular Research Center, Fimlab Laboratories, Tampere University and University Hospital, Tampere, Finland.
  • 6 Neuromuscular Research Center, Department of Neurology, Tampere University and University Hospital, Tampere, Finland.
  • 7 Division of Clinical Neurosciences, Department of Neurology, Turku University Hospital, Turku, Finland.
  • 8 Dipartimento di Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
  • 9 Section of Medical Genetics, Mater Dei Hospital, Msida, Malta.
  • 10 Department of Anatomy and Cell Biology, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
  • 11 Neuroscience Department, Mater Dei Hospital, Msida, Malta.
  • 12 Neuromuscular Disease Center AOC, University Hospital Nantes, Nantes, France.
  • 13 IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy.
  • 14 Department of Neurology, University Hospital Bonn, Bonn, Germany.
  • 15 AP-HP, Institute of Myology, Centre de Référence des Maladies Neuromusculaires, Hôpital Pitié-Salpêtrière, Paris, France.
  • 16 Neuromuscular Morphology Unit, Institute of Myology, Myology Research Centre INSERM, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
  • 17 Department of Pathology, Fimlab Laboratories, Tampere University Hospital, Tampere, Finland.
  • 18 Institute for Molecular Medicine Finland FIMM, Technology Centre, University of Helsinki, Helsinki, Finland.
  • 19 IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Disease Unit, Milan, Italy.
  • 20 Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
  • 21 Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
  • 22 Department of Neurology, Vaasa Central Hospital, Vaasa, Finland.
PMID: 33974137 DOI: 10.1007/s00401-021-02319-x
Abstract

Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent Cell Culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In Cell Culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.

Keywords

Amyloidogenesis; Distal myopathy; Proteinopathy; Stress granules; X-linked.

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