Transcriptional regulation differs in affected facioscapulohumeral muscular dystrophy patients compared to asymptomatic related carriers

Human Genome Research Center, Department of Genetics and Evolutive Biology, Institute of Biosciences, University of São Paulo, 05508-090, São Paulo, Brazil.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2009; 106(15):6220-5. DOI: 10.1073/pnas.0901573106
Source: PubMed


Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disorder that has been associated with a contraction of 3.3-kb repeats on chromosome 4q35. FSHD is characterized by a wide clinical inter- and intrafamilial variability, ranging from wheelchair-bound patients to asymptomatic carriers. Our study is unique in comparing the gene expression profiles from related affected, asymptomatic carrier, and control individuals. Our results suggest that the expression of genes on chromosome 4q is altered in affected and asymptomatic individuals. Remarkably, the changes seen in asymptomatic samples are largely in products of genes encoding several chemokines, whereas the changes seen in affected samples are largely in genes governing the synthesis of GPI-linked proteins and histone acetylation. Besides this, the affected patient and related asymptomatic carrier share the 4qA161 haplotype. Thus, these polymorphisms by themselves do not explain the pathogenicity of the contracted allele. Interestingly, our results also suggest that the miRNAs might mediate the regulatory network in FSHD. Together, our results support the previous evidence that FSHD may be caused by transcriptional dysregulation of multiple genes, in cis and in trans, and suggest some factors potentially important for FSHD pathogenesis. The study of the gene expression profiles from asymptomatic carriers and related affected patients is a unique approach to try to enhance our understanding of the missing link between the contraction in D4Z4 repeats and muscle disease, while minimizing the effects of differences resulting from genetic background.

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    • "Thus, even though the aim of our study was not to identify what distinguishes FSHD from normal muscle, it emerges that taking one “snapshot” of the pathologic process could be not enough to identify the process itself. This strict dependency on the timing and the muscle in which the “snapshot” is taken could have contributed to the diverse results obtained in different FSHD gene expression studies [14], [15], [27], [33]. This constitutes a substantial difference from, for instance, Duchenne muscular dystrophy, in which the molecular signature develops early and remains constant all over the disease course [12]. "
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