Key result
The presence of the mouse dystrophin muscle enhancer-1 (DME-1) activated the dystrophin cerebellar Purkinje promoter in skeletal muscle, but not in cardiac muscle, of transgenic mice.
The dystrophin muscle enhancer-1 (DME-1) activates the dystrophin CP promoter in skeletal muscle but not cardiac muscle, providing a potential mechanism for the lack of skeletal myopathy in X-linked dilated cardiomyopathy patients.
May explain cardiac selectivity without skeletal myopathy in XLDC; leaves open DME-1 targeting for human translation.
A subset of patients harboring mutations in the dystrophin gene suffer from X-linked dilated cardiomyopathy (XLCM), a familial heart disease that is not accompanied by any clinical signs of skeletal muscle myopathy. As the muscle (M) isoform of dystrophin is not expressed in these patients, the absence of skeletal muscle symptoms has been attributed to expression of the brain (B) and cerebellar Purkinje (CP) isoforms of dystrophin in skeletal, but not cardiac, muscles of XLCM patients. The compensatory mechanism of dystrophin B and CP promoter upregulation is not known but it has been suggested that the dystrophin muscle enhancer from intron 1, DME-1, may be important in this activity. Previous studies have shown that the presence of the DME-1 is essential for a significant increase in dystrophin B and CP promoter activity in skeletal muscle cells in culture. Here, we demonstrate that the mouse dystrophin CP promoter drives expression of a lacZ reporter gene specifically to the cerebellar Purkinje cell layer but not to skeletal or cardiac muscle of transgenic mice. However, if the mouse counterpart of DME-1 is present in the transgene construct, the dystrophin CP promoter is now activated in skeletal muscle, but not in cardiac muscle. Our findings provide in vivo evidence for the importance of the dystrophin muscle enhancer sequences in activating the dystrophin CP promoter in skeletal muscle. Furthermore, they provide support for the model in which muscle enhancers, like DME-1, activate the dystrophin B and CP promoters in skeletal muscle, but not in cardiac muscle, of XLCM patients.
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Repentigny et al. (2004) studied X-linked dilated cardiomyopathy (context). Transgene construct with mouse counterpart of DME-1 and dystrophin CP promoter vs. Transgene construct with dystrophin CP promoter without DME-1 was evaluated on Expression of a lacZ reporter gene in skeletal and cardiac muscle. The presence of the mouse dystrophin muscle enhancer-1 (DME-1) activated the dystrophin cerebellar Purkinje promoter in skeletal muscle, but not in cardiac muscle, of transgenic mice.
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