The transgenic expression of LARGE exacerbates the muscle phenotype of dystroglycanopathy mice
| Autor: | Dominic J. Wells, H. Booler, R L Terry, Callum Parr, M.R. Ackroyd, M. Fernandez-Fuente, J. Kim, Manoli Kavishwar, E. Lacey, K E Wells, C. Whitmore, Attia Ashraf, Francesco Muntoni, Susan C. Brown |
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| Rok vydání: | 2013 |
| Předmět: |
Central Nervous System
Glycosylation Transgene Cre recombinase N-Acetylglucosaminyltransferases Basement Membrane Article Mice SOX1 Laminin Transferases Genetics medicine Animals Pentosyltransferases Muscular dystrophy Dystroglycans Muscle Skeletal Molecular Biology Genetics (clinical) Mice Knockout Fukutin-related protein biology Proteins Walker-Warburg Syndrome General Medicine medicine.disease Phenotype Up-Regulation Disease Models Animal Immunology Mutation biology.protein Cancer research Limb-girdle muscular dystrophy |
| Zdroj: | Human molecular genetics. 23(7) |
| ISSN: | 1460-2083 |
| Popis: | Mutations in fukutin-related protein (FKRP) underlie a group of muscular dystrophies associated with the hypoglycosylation of α-dystroglycan (α-DG), a proportion of which show central nervous system involvement. Our original FKRP knock-down mouse (FKRPKD) replicated many of the characteristics seen in patients at the severe end of the dystroglycanopathy spectrum but died perinatally precluding its full phenotyping and use in testing potential therapies. We have now overcome this by crossing FKRPKD mice with those expressing Cre recombinase under the Sox1 promoter. Owing to our original targeting strategy, this has resulted in the restoration of Fkrp levels in the central nervous system but not the muscle, thereby generating a new model (FKRPMD) which develops a progressive muscular dystrophy resembling what is observed in limb girdle muscular dystrophy. Like-acetylglucosaminyltransferase (LARGE) is a bifunctional glycosyltransferase previously shown to hyperglycosylate α-DG. To investigate the therapeutic potential of LARGE up-regulation, we have now crossed the FKRPMD line with one overexpressing LARGE and show that, contrary to expectation, this results in a worsening of the muscle pathology implying that any future strategies based upon LARGE up-regulation require careful management. |
| Databáze: | OpenAIRE |
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