UMMS Affiliation

Division of Cell Biology and Imaging, Department of Radiology; Luna Lab

Publication Date


Document Type



Amino Acids, Peptides, and Proteins | Cardiovascular Diseases | Cell Biology | Cellular and Molecular Physiology | Molecular and Cellular Neuroscience | Musculoskeletal Diseases | Musculoskeletal, Neural, and Ocular Physiology | Nervous System Diseases | Neurology


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.


SVIL, cardiac disease, costameric protein, myopathy, supervillin

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© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (, which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact

DOI of Published Version



Hedberg-Oldfors C, Meyer R, Nolte K, Abdul Rahim Y, Lindberg C, Karason K, Thuestad IJ, Visuttijai K, Geijer M, Begemann M, Kraft F, Lausberg E, Hitpass L, Götzl R, Luna EJ, Lochmüller H, Koschmieder S, Gramlich M, Gess B, Elbracht M, Weis J, Kurth I, Oldfors A, Knopp C. Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles. Brain. 2020 Aug 1;143(8):2406-2420. doi: 10.1093/brain/awaa206. PMID: 32779703; PMCID: PMC7447519. Link to article on publisher's site

Journal/Book/Conference Title

Brain : a journal of neurology


Full author list omitted for brevity. For the full list of authors, see article.

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Creative Commons License

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License