Human Molecular Genetics Advance Access originally published online on September 30, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 22 2895-2907
DOI: 10.1093/hmg/ddg327
© 2003 Oxford University Press
Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation
1Department of Biological Chemistry, University of California, Irvine, CA, USA, 2Children's National Medical Center, Washington, DC, USA, 3Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 4Leiden University Medical Center, The Netherlands, 5National Institute for Neuroscience, Tokyo, Japan and 6Eccles Institute of Genetics, University of Utah, Salt Lake City, UT, USA
Received June 9, 2003; Accepted September 18, 2003
The neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD) results from integral deletions of the subtelomeric repeat D4Z4 on chromosome 4q. A disruption of chromatin structure affecting gene expression is thought to underlie the pathophysiology. The global gene expression profiling of mature muscle tissue presented here provides the first insight into an FSHD-specific defect in myogenic differentiation. FSHD expression profiles generated by oligonucleotide microarrays were compared with those from normal muscle as well as other types of muscular dystrophies (DMD, aSGD) in order to determine FSHD-specific changes. In addition, matched biopsies (affected and unaffected muscle) from individuals with FSHD served to monitor expression changes during the progression of the disease as well as to diminish non-specific changes resulting from individual variability. Among genes altered in an FSHD-specific and highly significant manner, many are involved in myogenic differentiation and suggest a partial block in the normal differentiation program. Indeed, many of the transcripts affected in FSHD represent direct targets of the transcription factor MyoD. Additional mis-expressed genes confirm a diminished capacity to buffer oxidative stress, as demonstrated in FSHD myoblasts. This enhanced vulnerability of proliferative stage myoblasts to reactive oxygen species is also disease-specific, further implicating a defect in FSHD muscle satellite cells. Importantly, none of the genes localizing to the FSHD region at 4q35 were found to exhibit a significantly altered pattern of expression in FSHD muscle. This finding was corroborated by expression analysis of FSHD muscle using a custom cDNA microarray containing 51 genes and ESTs from the 4q35 region. Disruptions in FSHD myogenesis and oxidative capacity may therefore not arise from a position effect mechanism as has been previously suggested, but rather from a global effect on gene regulation. Improper nuclear localization of 4qter is discussed as an alternative model for FSHD gene regulation and pathogenesis.
* To whom correspondence should be addressed at: Department of Biological Chemistry, 202 Sprague Hall, University of California, Irvine, CA 92697, USA. Tel: +1 9498242750; Fax: +1 9498249547; Email: stwinoku{at}uci.edu
Present address: Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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