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Abstract

Objective

The dose–response effects of dysferlin transgenesis were analyzed to determine if the dysferlin-deficient myopathies are good candidates for gene replacement therapy.

Methods

We have generated 3 lines of transgenic mice, expressing low, mid, and high levels of full-length human dysferlin from a muscle-specific promoter. Transgenic skeletal muscle was analyzed and scored for morphological and functional deficits.

Results

Overexpression of dysferlin in mice resulted in a striking phenotype of kyphosis, irregular gait, and reduced muscle mass and strength. Moreover, protein dosage correlated with phenotype severity. In contrast to dysferlin-null skeletal muscle, no evidence of sarcolemmal impairment was revealed. Rather, increased levels of Ca2+-regulated, dysferlin-binding proteins and endoplasmic reticulum stress chaperone proteins were observed in muscle lysates from transgenic mice as compared with controls.

Interpretation

Expression levels of dysferlin are important for appropriate function without deleterious or cytotoxic effects. As a corollary, we propose that future endeavors in gene replacement for correction of dysferlinopathy should be tailored to take account of this. ANN NEUROL 2010;67:384–393