Abstract
Spontaneous and engineered mouse mutants have facilitated our understanding of the pathogenesis of muscular dystrophy and they provide models for the development of therapeutic approaches1. The mouse myodystrophy (myd) mutation produces an autosomal recessive, neuromuscular phenotype2. Homozygotes have an abnormal gait, show abnormal posturing when suspended by the tail and are smaller than littermate controls. Serum creatine kinase is elevated and muscle histology is typical of a progressive myopathy with focal areas of acute necrosis and clusters of regenerating fibers3. Additional aspects of the phenotype include sensorineural deafness, reduced lifespan and decreased reproductive fitness2,3. The myd mutation maps to mouse chromosome 8 at approximately 33 centimorgans (cM) (refs. 2, 4–7). Here we show that the gene mutated in myd encodes a glycosyltransferase, Large. The human homolog of this gene (LARGE) maps to chromosome 22q. In myd, an intragenic deletion of exons 4–7 causes a frameshift in the resultant mRNA and a premature termination codon before the first of the two catalytic domains. On immunoblots, a monoclonal antibody to α-dystroglycan (a component of the dystrophin-associated glycoprotein complex) shows reduced binding in myd, which we attribute to altered glycosylation of this protein. We speculate that abnormal post-translational modification of α-dystroglycan may contribute to the myd phenotype.
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Acknowledgements
We thank M. Hamshere and P. Scotting for helpful discussions and insightful comments on the manuscript, S. Kröger for generously providing antibody and M. Bucan for access to RPCI BAC library filters. We acknowledge the Wellcome Trust for a travel grant to P.K.G. This work was also supported by the Austrian Verein zur Erforschung der Muskelerkrankungen bei Kindern (P.J.H.) and by grant SFB Nr. 006-F613 from the Austrian Science Research Foundation (R.E.B.).
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Grewal, P., Holzfeind, P., Bittner, R. et al. Mutant glycosyltransferase and altered glycosylation of α-dystroglycan in the myodystrophy mouse. Nat Genet 28, 151–154 (2001). https://doi.org/10.1038/88865
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DOI: https://doi.org/10.1038/88865
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