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Gamma-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin.

Authors
  • Hack, A A1
  • Ly, C T
  • Jiang, F
  • Clendenin, C J
  • Sigrist, K S
  • Wollmann, R L
  • McNally, E M
  • 1 Department of Molecular Genetics and Cell Biology, Section of Cardiology, University of Chicago, Chicago, Illinois 60637, USA.
Type
Published Article
Journal
Journal of Cell Biology
Publisher
Rockefeller University Press
Publication Date
Sep 07, 1998
Volume
142
Issue
5
Pages
1279–1287
Identifiers
PMID: 9732288
Source
Medline
Language
English
License
Unknown

Abstract

gamma-Sarcoglycan is a transmembrane, dystrophin-associated protein expressed in skeletal and cardiac muscle. The murine gamma-sarcoglycan gene was disrupted using homologous recombination. Mice lacking gamma-sarcoglycan showed pronounced dystrophic muscle changes in early life. By 20 wk of age, these mice developed cardiomyopathy and died prematurely. The loss of gamma-sarcoglycan produced secondary reduction of beta- and delta-sarcoglycan with partial retention of alpha- and epsilon-sarcoglycan, suggesting that beta-, gamma-, and delta-sarcoglycan function as a unit. Importantly, mice lacking gamma-sarco- glycan showed normal dystrophin content and local- ization, demonstrating that myofiber degeneration occurred independently of dystrophin alteration. Furthermore, beta-dystroglycan and laminin were left intact, implying that the dystrophin-dystroglycan-laminin mechanical link was unaffected by sarcoglycan deficiency. Apoptotic myonuclei were abundant in skeletal muscle lacking gamma-sarcoglycan, suggesting that programmed cell death contributes to myofiber degeneration. Vital staining with Evans blue dye revealed that muscle lacking gamma-sarcoglycan developed membrane disruptions like those seen in dystrophin-deficient muscle. Our data demonstrate that sarcoglycan loss was sufficient, and that dystrophin loss was not necessary to cause membrane defects and apoptosis. As a common molecular feature in a variety of muscular dystrophies, sarcoglycan loss is a likely mediator of pathology.

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