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Published online 11 December 2000. doi:10.1083/jcb.151.6.1321
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© The Rockefeller University Press, 0021-9525/2000//1321 $5.00
The Journal of Cell Biology, Volume 151, Number 6, , 2000 1321-1336

Original Article

Expression Profiling in the Muscular Dystrophies

: Identification of Novel Aspects of Molecular Pathophysiology



Yi-Wen Chena, Po Zhaoa, Rehannah Borupa, and Eric P. Hoffmana

a Research Center for Genetic Medicine, Children's National Medical Center, George Washington University, Washington, DC 20010
Research Center for Genetic Medicine, CNMC, 111 Michigan Ave. NW, Washington DC 20010.(202) 884-6014(202) 884-6011

ehoffman{at}cnmc.org

We used expression profiling to define the pathophysiological cascades involved in the progression of two muscular dystrophies with known primary biochemical defects, dystrophin deficiency (Duchenne muscular dystrophy) and {alpha}-sarcoglycan deficiency (a dystrophin-associated protein). We employed a novel protocol for expression profiling in human tissues using mixed samples of multiple patients and iterative comparisons of duplicate datasets. We found evidence for both incomplete differentiation of patient muscle, and for dedifferentiation of myofibers to alternative lineages with advancing age. One developmentally regulated gene characterized in detail, {alpha}-cardiac actin, showed abnormal persistent expression after birth in 60% of Duchenne dystrophy myofibers. The majority of myofibers (~80%) remained strongly positive for this protein throughout the course of the disease. Other developmentally regulated genes that showed widespread overexpression in these muscular dystrophies included embryonic myosin heavy chain, versican, acetylcholine receptor {alpha}-1, secreted protein, acidic and rich in cysteine/osteonectin, and thrombospondin 4. We hypothesize that the abnormal Ca2+ influx in dystrophin- and {alpha}-sarcoglycan–deficient myofibers leads to altered developmental programming of developing and regenerating myofibers. The finding of upregulation of HLA-DR and factor XIIIa led to the novel identification of activated dendritic cell infiltration in dystrophic muscle; these cells mediate immune responses and likely induce microenvironmental changes in muscle. We also document a general metabolic crisis in dystrophic muscle, with large scale downregulation of nuclear-encoded mitochondrial gene expression. Finally, our expression profiling results show that primary genetic defects can be identified by a reduction in the corresponding RNA.

Key Words: muscular dystrophy • microarray • dystrophin • {alpha}-sarcoglycan • expression profiling

© 2000 The Rockefeller University Press

The online version of this article contains supplemental material.

Abbreviations used in this paper: {alpha}-SGD, {alpha}-sarcoglycan deficiency; C3, complement component 3; DMD, Duchenne muscular dystrophy; MM, mismatch; PM, perfect match; SPARC, secreted protein, acidic and rich in cysteine.


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