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Overexpression of γ-Sarcoglycan Induces Severe Muscular Dystrophy
Open accessAbstract
The sarcoglycan complex is found normally at the plasma membrane of muscle. Disruption of the sarcoglycan complex, through primary gene mutations in dystrophin or sarcoglycan subunits, produces membrane instability and muscular dystrophy. Restoration of the sarcoglycan complex at the plasma membrane requires reintroduction of the mutant sarcoglycan subunit in a manner that will permit normal assembly of the entire sarcoglycan complex. To study sarcoglycan gene replacement, we introduced transgenes expressing murine gamma-sarcoglycan into muscle of normal mice. Mice expressing high levels of gamma-sarcoglycan, under the control of the muscle-specific creatine kinase promoter, developed a severe muscular dystrophy with greatly reduced muscle mass and early lethality. Marked gamma-sarcoglycan overexpression produced cytoplasmic aggregates that interfered with normal membrane targeting of gamma-sarcoglycan. Overexpression of gamma-sarcoglycan lead to the up-regulation of alpha- and beta-sarcoglycan. These data suggest that increased gamma-sarcoglycan and/or mislocalization of gamma-sarcoglycan to the cytoplasm is sufficient to induce muscle damage and provides a new model of muscular dystrophy that highlights the importance of this protein in the assembly, function, and downstream signaling of the sarcoglycan complex. Most importantly, gene dosage and promoter strength should be given serious consideration in replacement gene therapy to ensure safety in human clinical trials.
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Increased levels of some proteins have been reported to cause myopathic symptoms, as shown in transgenic mouse lines overexpressing caveolin-3 or gamma-sarcoglycan.
“Increased levels of some proteins have been reported to cause myopathic symptoms, as has been shown in work involving transgenic mouse lines that overexpress either caveolin-3 (Galbiati et al. 2000) or g -sarcoglycan (Zhu et al. 2001).”
From Limb-Girdle Muscular Dystrophy Type 2H Associated with Mutation in TRIM32, a Putative E3-Ubiquitin–Ligase Gene (2002) · cites this paper as Zhu et al. 2001
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Metadata
- Authors
- Zhu, X., Hadhazy, M., Groh, M. E., Wheeler, M. T., Wollmann, R., & McNally, E. M.
- Affiliations
- University of Chicago (US)
- Corresponding author
- McNally, Elizabeth M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-06
- Volume
- 276
- Issue
- 24
- Pages
- 21785-21790
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2069791967
- Cited by
- 56
- References
- 30
- Citations by year
- 2023: 3 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 6 · 2014: 2 · 2013: 2
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association (HL61322)
- National Institutes of Health (5f32hl010288-02)
- National Heart, Lung, and Blood Institute (HL 61322, R01HL061322, HL10288)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
- Keywords
- gamma-sarcoglycan, sarcoglycan complex, muscular dystrophy, gene overexpression, gene replacement therapy, transgenic mice, cytoplasmic aggregates, alpha-sarcoglycan, beta-sarcoglycan, gene dosage, membrane targeting, dystrophin
- MeSH terms
- Animals, Cattle, Cytoskeletal Proteins, Gene Expression Regulation, Membrane Glycoproteins, Mice, Transgenic, Muscular Dystrophy, Animal, Mutation, Myocardium, Dystrophin, Muscle, Skeletal, Muscle Fibers, Fast-Twitch, Dystroglycans, Sarcoglycans, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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