Human Molecular Genetics Advance Access originally published online on September 22, 2004
Human Molecular Genetics 2004 13(22):2853-2862; doi:10.1093/hmg/ddh305
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Human Molecular Genetics, Vol. 13, No. 22 © Oxford University Press 2004; all rights reserved
The mouse dystrophin muscle enhancer-1 imparts skeletal muscle, but not cardiac muscle, expression onto the dystrophin Purkinje promoter in transgenic mice
1Ottawa Health Research Institute, University of Ottawa Center for Neuromuscular Disease, Ottawa, Ontario, Canada K1H 8L6, 2Department of Biochemistry, Microbiology and Immunology, 3Department of Cellular and Molecular Medicine and 4Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5
Received July 26, 2004; Accepted September 15, 2004
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.
* To whom correspondence should be addressed at: Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6. Tel: +1 6137378707; Fax: +1 6137378803; Email: rkothary{at}ohri.ca