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Transgenic Overexpression of LARGE Induces alpha-Dystroglycan Hyperglycosylation in Skeletal and Cardiac Muscle

Brockington, M; Torelli, S; Sharp, PS; Liu, K; Cirak, S; Brown, SC; Wells, DJ; (2010) Transgenic Overexpression of LARGE Induces alpha-Dystroglycan Hyperglycosylation in Skeletal and Cardiac Muscle. PLOS ONE , 5 (12) , Article e14434. 10.1371/journal.pone.0014434. Green open access

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Abstract

Background: LARGE is one of seven putative or demonstrated glycosyltransferase enzymes defective in a common group of muscular dystrophies with reduced glycosylation of alpha-dystroglycan. Overexpression of LARGE induces hyperglycosylation of alpha-dystroglycan in both wild type and in cells from dystroglycanopathy patients, irrespective of their primary gene defect, restoring functional glycosylation. Viral delivery of LARGE to skeletal muscle in animal models of dystroglycanopathy has identical effects in vivo, suggesting that the restoration of functional glycosylation could have therapeutic applications in these disorders. Pharmacological strategies to upregulate Large expression are also being explored.Methodology/Principal Findings: In order to asses the safety and efficacy of long term LARGE over-expression in vivo, we have generated four mouse lines expressing a human LARGE transgene. On observation, LARGE transgenic mice were indistinguishable from the wild type littermates. Tissue analysis from young mice of all four lines showed a variable pattern of transgene expression: highest in skeletal and cardiac muscles, and lower in brain, kidney and liver. Transgene expression in striated muscles correlated with alpha-dystroglycan hyperglycosylation, as determined by immunoreactivity to antibody IIH6 and increased laminin binding on an overlay assay. Other components of the dystroglycan complex and extracellular matrix ligands were normally expressed, and general muscle histology was indistinguishable from wild type controls. Further detailed muscle physiological analysis demonstrated a loss of force in response to eccentric exercise in the older, but not in the younger mice, suggesting this deficit developed over time. However this remained a subclinical feature as no pathology was observed in older mice in any muscles including the diaphragm, which is sensitive to mechanical load-induced damage.Conclusions/Significance: This work shows that potential therapies in the dystroglycanopathies based on LARGE upregulation and alpha-dystroglycan hyperglycosylation in muscle should be safe.

Type: Article
Title: Transgenic Overexpression of LARGE Induces alpha-Dystroglycan Hyperglycosylation in Skeletal and Cardiac Muscle
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0014434
Publisher version: http://dx.doi.org/10.1371/journal.pone.0014434
Language: English
Additional information: © 2010 Brockington et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was supported by the Institute of Child Health and Great Ormond Street Hospitals Biomedical Research Centre (BRC 08DN25) to FM, Association Francaise contres les Myopathies (AFM 1399 to FM, AFM 13992 and 14175 to SCB) and Muscular Dystrophy Association of America (MDA 68721 to FM). MB was the recipient of a Wellcome Trust Value in People award. FM is supported by Great Ormond Street Hospital Children's Charity. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: CONGENITAL MUSCULAR-DYSTROPHY, WALKER-WARBURG-SYNDROME, HUMAN LARGE GENE, LAMININ-BINDING, PROTEIN GENE, DEFECTIVE GLYCOSYLATION, ABNORMAL GLYCOSYLATION, MENTAL-RETARDATION, LARGE FAMILY, O-GLYCAN
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
URI: https://discovery.ucl.ac.uk/id/eprint/703521
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