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Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles

Hedberg-Oldfors, Carola ; Meyer, Robert ; Nolte, Kay ; Abdul Rahim, Yassir LU orcid ; Lindberg, Christopher ; Karason, Kristjan ; Thuestad, Inger Johanne ; Visuttijai, Kittichate ; Geijer, Mats LU and Begemann, Matthias , et al. (2020) In Brain : a journal of neurology 143(8). p.2406-2420
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
SVIL, cardiac disease, costameric protein, myopathy, supervillin
in
Brain : a journal of neurology
volume
143
issue
8
pages
15 pages
publisher
Oxford University Press
external identifiers
  • scopus:85090073157
  • pmid:32779703
ISSN
1460-2156
DOI
10.1093/brain/awaa206
language
English
LU publication?
yes
id
5c1aff5c-c9ff-4b08-831d-a8cd5b87d1eb
date added to LUP
2020-09-22 14:26:46
date last changed
2024-06-12 20:42:14
@article{5c1aff5c-c9ff-4b08-831d-a8cd5b87d1eb,
  abstract     = {{<p>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.</p>}},
  author       = {{Hedberg-Oldfors, Carola and Meyer, Robert and Nolte, Kay and Abdul Rahim, Yassir and Lindberg, Christopher and Karason, Kristjan and Thuestad, Inger Johanne and Visuttijai, Kittichate and Geijer, Mats and Begemann, Matthias and Kraft, Florian and Lausberg, Eva and Hitpass, Lea and Götzl, Rebekka and Luna, Elizabeth J. and Lochmüller, Hanns and Koschmieder, Steffen and Gramlich, Michael and Gess, Burkhard and Elbracht, Miriam and Weis, Joachim and Kurth, Ingo and Oldfors, Anders and Knopp, Cordula}},
  issn         = {{1460-2156}},
  keywords     = {{SVIL; cardiac disease; costameric protein; myopathy; supervillin}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{8}},
  pages        = {{2406--2420}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain : a journal of neurology}},
  title        = {{Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles}},
  url          = {{http://dx.doi.org/10.1093/brain/awaa206}},
  doi          = {{10.1093/brain/awaa206}},
  volume       = {{143}},
  year         = {{2020}},
}