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Loss of Supervillin Causes Myopathy with Myofibrillar Disorganization and Autophagic Vacuoles

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Loss of Supervillin Causes Myopathy with Myofibrillar Disorganization and Autophagic Vacuoles University of Massachusetts Medical School eScholarship@UMMS Open Access Articles Open Access Publications by UMMS Authors 2020-08-01 Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles Carola Hedberg-Oldfors University of Gothenburg Et al. Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/oapubs Part of the Amino Acids, Peptides, and Proteins Commons, Cardiovascular Diseases Commons, Cell Biology Commons, Cellular and Molecular Physiology Commons, Molecular and Cellular Neuroscience Commons, Musculoskeletal Diseases Commons, Musculoskeletal, Neural, and Ocular Physiology Commons, Nervous System Diseases Commons, and the Neurology Commons Repository Citation Hedberg-Oldfors C, Luna EJ, Oldfors A, Knopp C. (2020). Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles. Open Access Articles. https://doi.org/10.1093/ brain/awaa206. Retrieved from https://escholarship.umassmed.edu/oapubs/4320 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Open Access Articles by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. doi:10.1093/brain/awaa206 BRAIN 2020: 143; 2406–2420 | 2406 Loss of supervillin causes myopathy with Downloaded from https://academic.oup.com/brain/article/143/8/2406/5890852 by Medical Center Library user on 17 September 2020 myofibrillar disorganization and autophagic vacuoles 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 Go¨tzl,10 Elizabeth J. Luna,11 Hanns Lochmu¨ller,12,13 Steffen Koschmieder,14 Michael Gramlich,15 Burkhard Gess,16 Miriam Elbracht,2 Joachim Weis,3 Ingo Kurth,2 Anders Oldfors1 and Cordula Knopp2 *These authors contributed equally to this work. 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, con- sanguineous 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 fea- tures. 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 immunohis- tochemical 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 super- villin (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. 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 Received January 25, 2020. Revised April 16, 2020. Accepted May 7, 2020 VC 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 (http://creativecommons.org/licenses/by-nc/4.0/), 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 [email protected] Loss of supervillin causes myopathy BRAIN 2020: 143; 2406–2420 | 2407 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 Correspondence to: Anders Oldfors Department of Pathology and Genetics, Sahlgrenska Academy, University of Gothenburg Gothenburg, Sweden E-mail: [email protected] Downloaded from https://academic.oup.com/brain/article/143/8/2406/5890852 by Medical Center Library user on 17 September 2020 Correspondence may also be addressed to: Cordula Knopp Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany E-mail: [email protected] Keywords: SVIL; supervillin; myopathy; costameric protein; cardiac disease Abbreviations: ERK = extracellular-signal-regulated kinase; LC3 = microtubule-associated protein 1A/1B-light chain 3; SV2 = supervillin isoform 2, muscle specific we report four patients from two unrelated families with Introduction homozygous loss-of-function mutations in SVIL. The Supervillin, encoded by the SVIL gene, is a large eukaryotic patients presented with myopathy and mild cardiac involve- protein from the villin/gelsolin superfamily of actin-binding ment and share a characteristic muscle pathology with lobu- proteins (Pestonjamasp et al.,1997) that is involved in many lated fibres and other structural abnormalities. cellular processes. Among others, supervillin regulates cyto- kinesis (Smith et al., 2010, 2013), cell adhesion (Takizawa et al.,2006) and cell motility (Fang et al.,2010) and pro- Material and methods motes cell survival through control of p53 levels (Fang and Luna, 2013). Supervillin mRNAs are expressed in most Patients and clinical evaluation human tissues, but are most abundant in skeletal muscle, fol- lowed by the heart and organs containing secretory or Two families with two affected siblings with myopathy, re- smooth muscle cells (Pope et al.,1998). In cardiac and skel- spectively, were investigated clinically, morphologically and etal muscle, the 250-kDa muscle-specific isoform of supervil- genetically. Family 1 originates from Lebanon and Family 2 lin (SV2), also called archvillin, is predominantly expressed from Turkey. The study complied with the Declaration of (Pope et al.,1998; Oh et al.,2003; Fang and Luna, 2013). Helsinki, and informed consent was obtained from all indi- Supervillin (SV2) is localized at the ends of differentiating viduals included in this study. Medical history taking and myotubes (Oh et al.,2003) and plays a role in myofibrillar physical examination were focused on neuromuscular and assembly (Lee et al.,2007). There is evidence for co-localiza- cardiac symptoms and signs. A summarized overview of the tion and interaction of supervillin (SV2) with structural pro- clinical phenotypes of all four patients is provided in teins in costameres and sarcomeres, which are important Table 1. components of cardiac and skeletal muscle cells (Oh et al., 2003; Lee et al.,2007, 2008; Spinazzola et al.,2015). Muscle MRI Among others, there are interactions with nebulin, dystroph- Magnetic resonance examinations were performed in all in and c-sarcoglycan, for which distinct and often severe four patients according to protocols described in the human muscular disorders are well known. For example, Supplementary material. mutations in nebulin account for about 50% of patients with congenital nemaline myopathy (Romero and Clarke, Morphological analysis 2013). Genetic variants in costameric proteins, such as dys- trophin, cause cardiac and skeletal muscle disorders (Nigro Skeletal muscle biopsy was performed in all four patients. and Piluso, 2015).
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