Mutant glycosyltransferase and altered glycosylation of α-dystroglycan in the myodystrophy mouse

Spontaneous and engineered mouse mutants have facilitated our understanding of the pathogenesis of muscular dystrophy and they provide models for the development of therapeutic approaches'. The mouse myodystrophy (myd) mutation produces an autosomal recessive, neuromuscular phenotype(2). 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 fibers(3). Additional aspects of the phenotype include sensorineural deafness, reduced lifespan and decreased reproductive fitness(2,3). 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 alpha -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 posttranslational modification of alpha -dystroglycan may contribute to the myd phenotype.