FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy
| Autor: | Christoph Krisp, Carmen Sonntag, L. Hersey, A.J. Wood, Sara Gibertini, Alex J. Fulcher, Patricia R. Jusuf, A. Siegel, Marina Mora, Chi-Hung Lin, Peter D. Currie, Stefanie Dudczig, Sara Alaei, Nicolle H. Packer, M. Li, K. Nishtala, Lee B. Miles, Paul J. Conroy, Fernando J. Rossello |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Glycosylation Glycobiology General Physics and Astronomy Skeletal muscle medicine.disease_cause Basement Membrane Muscular Dystrophies Extracellular matrix chemistry.chemical_compound Gene Knockout Techniques 0302 clinical medicine Muscular dystrophy Zebrafish Uncategorized Mutation Multidisciplinary biology Neuromuscular disease Phenotype Cell biology musculoskeletal diseases Myoblasts Skeletal Science General Biochemistry Genetics and Molecular Biology Article Cell Line 03 medical and health sciences medicine Animals Humans Pentosyltransferases Muscle Skeletal Glycosyltransferases General Chemistry Muscular Dystrophy Animal Zebrafish Proteins medicine.disease biology.organism_classification Fukutin Fibronectins Fibronectin Disease Models Animal 030104 developmental biology chemistry Muscular Dystrophies Limb-Girdle biology.protein 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG’s glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies. FKRP mutations cause muscular dystrophies with varied clinical presentations. The target of FKRP is α-dystroglycan, but here the authors show that FKRP also directs sialylation of fibronectin, a process that is essential for recruitment o collagen to the muscle basement membrane. |
| Databáze: | OpenAIRE |
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