Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles

Brain. 2020 Aug 1;143(8):2406-2420. doi: 10.1093/brain/awaa206.

Carola Hedberg-Oldfors ¹, Robert Meyer ², Kay Nolte ³, Yassir Abdul Rahim ¹, Christopher Lindberg ⁴, Kristjan Karason ⁵, Inger Johanne Thuestad ⁶, Kittichate Visuttijai ¹, Mats Geijer ⁷ ⁸, Matthias Begemann ², Florian Kraft ², Eva Lausberg ², Lea Hitpass ⁹, Rebekka Götzl ¹⁰, Elizabeth J Luna ¹¹, Hanns Lochmüller ¹² ¹³, Steffen Koschmieder ¹⁴, Michael Gramlich ¹⁵, Burkhard Gess ¹⁶, Miriam Elbracht ², Joachim Weis ³, Ingo Kurth ², Anders Oldfors ¹, Cordula Knopp ²

Affiliations

1 Department of Pathology and Genetics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
2 Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.
3 Institute of Neuropathology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
4 Department of Neurology, Neuromuscular Centre, Sahlgrenska University Hospital, Gothenburg, Sweden.
5 Department of Cardiology and Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden.
6 Department of Pediatrics, Skane University Hospital, Malmo, Sweden.
7 Department of Radiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
8 Department of Clinical Sciences, Lund University, Lund, Sweden.
9 Department of Diagnostic and Interventional Radiology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
10 Department of Plastic Surgery, Hand and Burn Surgery, Medical Faculty, RWTH Aachen University, Aachen, Germany.
11 Division of Cell Biology and Imaging, Department of Radiology, University of Massachusetts Medical School, Worcester, USA.
12 Children's Hospital of Eastern Ontario Research Institute, Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada.
13 Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada.
14 Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.
15 Department of Invasive Electrophysiology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
16 Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany.

PMID: 32779703 DOI: 10.1093/brain/awaa206

Abstract

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.

Keywords

SVIL; cardiac disease; costameric protein; myopathy; supervillin.

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