Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles

Research output: Contribution to journalArticle


The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy.


  • Carola Hedberg-Oldfors
  • Robert Meyer
  • Kay Nolte
  • Yassir Abdul Rahim
  • Christopher Lindberg
  • Kristjan Karason
  • Inger Johanne Thuestad
  • Kittichate Visuttijai
  • Matthias Begemann
  • Florian Kraft
  • Eva Lausberg
  • Lea Hitpass
  • Rebekka Götzl
  • Elizabeth J. Luna
  • Hanns Lochmüller
  • Steffen Koschmieder
  • Michael Gramlich
  • Burkhard Gess
  • Miriam Elbracht
  • Joachim Weis
  • Ingo Kurth
  • Anders Oldfors
  • Cordula Knopp
External organisations
  • Sahlgrenska University Hospital
  • Skåne University Hospital
  • University of Ottawa
  • University of Gothenburg
  • RWTH Aachen University
  • University of Massachusetts Medical School
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology


  • SVIL, cardiac disease, costameric protein, myopathy, supervillin
Original languageEnglish
Pages (from-to)2406-2420
Number of pages15
JournalBrain : a journal of neurology
Issue number8
Publication statusPublished - 2020 Aug 1
Publication categoryResearch