Sarcoglycanopathies LGMD2CF

Sarcoglycans are transmembrane glycoproteins that form a subcomplex within the DGC, creating a link between the cytoskeleton of the myocyte and the extracellular matrix. The Bio14.6 hamster was originally identified in 1962 as a spontaneous myopathy model having both skeletal and cardiac muscle involvement (Homburger et al. 1962). Prior to the identification of the causative gene locus, Bio14.6 was utilized as a cardiomyopathy model since the heart muscle is more affected than the skeletal muscle (Vainzof et al. 2008). Bio14.6 hamsters develop muscle fiber necrosis in the myocardium and the skeletal muscle. There is hypertrophy of myocardium ultimately leading to heart failure. Skeletal muscles also show significant degeneration. With the identification of a mutation consisting of the deletion of regulatory sequences and the first exon of 5-sarcoglycan, Bio14.6 was recognized as a model of LGMD2F (Nigro et al. 1997). However, unlike

Bio14.6, in the majority of human sarcoglycanopathy patients there is no evidence of cardiomyopathy (Nigro et al. 1997). In Bio14.6 animals there is a secondary reduction of a-, b-, and g-sarcoglycan proteins. The variability in the reduction of expression of a-dystroglycan among Bio14.6 hamsters may account for the variable disease course, from the slowly progressive to rapid progression to death. Human sarcoglycanopathy patients share similar findings with respect to the progression of disease (Shelton and Engvall, 2005).

Knockout mice for each of the sarcoglycan genes (g, a, b, 8-sarcoglycan), LGMD2C-F respectively, have been generated. Although each model exhibits progressive muscular dystrophy with varying severity, every model shares a secondary concomitant reduction of all other sarcoglycan proteins as well as other components of the DGC (Vainzof et al. 2008). The severity of dystrophic changes is comparable to those seen in mdx mice, except for the moderately affected sarcogly-can-a deficient mice.

Sarcoglycan-a null mice (sgca-null) do not show clinical signs of myopathy, despite the dystrophic evidence present on histopathological analysis (Duclos et al. 1998). Both sarcoglycan-b null (sgcb-null) and sarcoglycan-8 null (sgcd-null) mice exhibit more severe dystrophic changes on histopathological examination (Coral-Vasquez et al. 1999; Durbeej et al. 2000). These mice have larger and more pronounced areas of necrosis as well as central nuclei, calcification, fibrosis, and massive fatty infiltration. Cardiomyopathy is also present in both these models indicated by prominent areas of myocardial necrosis. In addition, these models exhibit disrupted expression of the DGC in smooth muscles due to the absence of b- and 8 sarcoglycan, which are normally present in smooth muscles. This leads to vascular irregularities in the sgcb-null and sgcd-null models. Sgca, sgcb, and sgcd all demonstrate increased muscle mass and contraction-induced injury. The sarcoglycan-g null (sgcg null) mice also demonstrate severe muscular dystrophy and cardiomyo-pathy. In contrast with the other sarcoglycan deficient models, sgcg mice do not show alteration in the expression of dystroglycans of the DGC, nor do they exhibit contraction-induced injury (Durbeej and Campbell, 2002). These murine models are valuable tools to evaluate therapeutic approaches as well as to further elucidate the role of each specific sarcoglycan.

Although specific mutations have not been identified, sarcoglycan deficiencies have been identified in a Boston Terrier, a Cocker Spaniel, and a Chihuahua. All three dogs exhibited failure to thrive, lethargy and exercise intolerance. Blood work results showed elevated creatine kinase (CK), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) indicating muscular damage. Histopathology showed varying fiber types, clusters of degeneration and regeneration with deposits of calcification. Immunohistochemistry demonstrated extremely reduced a, b, and g-sarcoglycan expression (Schatzberg et al. 2003). These animals are the only report of sarcoglycanopathy in intermediate models and present the opportunity to study therapies in a model that closely resembles the human patient.

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