Muscular dystrophy is caused by mutations in the genes that code for the proteins that form a structural bridge between muscle cells and the extracellular matrix (ECM). Loss of this bridge causes deterioration of the skeletal muscles. Mutations in fukutin cause Fukuyama congenital muscular dystrophy, one of the most common autosomal-recessive disorders in Japan. In this article, Beedle et al. generated mice with a fukutin gene that could be disrupted at different points during embryonic development. In these frames, muscle tissue from wild-type mice and mice with disrupted fukutin is stained for dystrophin-glycoprotein complexes, which are required for tissue integrity.
Dystroglycan is a transmembrane glycoprotein that links the extracellular basement membrane to cytoplasmic dystrophin. Disruption of the extensive carbohydrate structure normally present on α-dystroglycan causes an array of congenital and limb girdle muscular dystrophies known as dystroglycanopathies. The essential role of dystroglycan in development has hampered elucidation of the mechanisms underlying dystroglycanopathies. Here, we developed a dystroglycanopathy mouse model using inducible or muscle-specific promoters to conditionally disrupt fukutin (Fktn), a gene required for dystroglycan processing. In conditional Fktn-KO mice, we observed a near absence of functionally glycosylated dystroglycan within 18 days of gene deletion. Twenty-week-old KO mice showed clear dystrophic histopathology and a defect in glycosylation near the dystroglycan O-mannose phosphate, whether onset of Fktn excision driven by muscle-specific promoters occurred at E8 or E17. However, the earlier gene deletion resulted in more severe phenotypes, with a faster onset of damage and weakness, reduced weight and viability, and regenerating fibers of smaller size. The dependence of phenotype severity on the developmental timing of muscle Fktn deletion supports a role for dystroglycan in muscle development or differentiation. Moreover, given that this conditional Fktn-KO mouse allows the generation of tissue- and timing-specific defects in dystroglycan glycosylation, avoids embryonic lethality, and produces a phenotype resembling patient pathology, it is a promising new model for the study of secondary dystroglycanopathy.
Aaron M. Beedle, Amy J. Turner, Yoshiaki Saito, John D. Lueck, Steven J. Foltz, Marisa J. Fortunato, Patricia M. Nienaber, Kevin P. Campbell