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: 9.81). 05/2009; 106(15):6220-5. DOI: 10.1073/pnas.0901573106
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Iris Eisenberg, Jul 22, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: The polystyrene based barium–magnesium (BMP) composite membrane was prepared by sol–gel method. The physico-chemical characterization of the BMP composite membrane was established by XRD, FTIR and simultaneous SEM studies. The membrane was found to be crystalline in nature with uniform arrangement of particles indicating no sign of visible cracks. Membrane potential is a measurable and important parameter to characterize the charge property of the membrane. Membrane potentials have been measured across the polystyrene based barium–magnesium (BMP) composite membrane separating various 1:1 electrolytes at different concentrations and followed the order KCl
    Arabian Journal of Chemistry 07/2011; 54. DOI:10.1016/j.arabjc.2011.07.022 · 2.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In vertebrates, overexpression of facioscapulohumeral muscular dystrophy (FSHD) region gene 1 (FRG1) recapitulates the pathophysiology exhibited by FSHD patients, although the role of FRG1 in FSHD remains controversial and no precise function for FRG1 has been described in any organism. To gain insight into the function and potential role of FRG1 in FSHD, we analyzed the highly conserved Caenorhabditis elegans ortholog, frg-1. C. elegans body-wall muscles contain two distinct subcellular pools of FRG-1: nuclear FRG-1, concentrated in the nucleoli; and cytoplasmic FRG-1, associated with the Z-disk and costamere-like structures known as dense bodies. Functionally, we demonstrate that FRG-1 is an F-actin-bundling protein, consistent with its localization to dense bodies; this activity is conserved in human FRG1. This is particularly intriguing because it places FRG-1 along side the list of dense-body components whose vertebrate orthologs are involved in the myriad myopathies associated with disrupted costameres and Z-disks. Interestingly, overexpressed FRG-1 preferentially accumulates in the nucleus and, when overexpressed specifically from the frg-1 promoter, disrupts the adult ventral muscle structure and organization. Together, these data further support a role for FRG1 overexpression in FSHD pathophysiology and reveal the previously unsuspected direct involvement of FRG-1 in muscle structure and integrity.
    Journal of Cell Science 03/2010; 123(Pt 7):1116-23. DOI:10.1242/jcs.058958 · 5.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy with a peculiar etiology. Unlike most genetic disorders, FSHD is not caused by mutations in a protein-coding gene. Instead, it is associated with contraction of the D4Z4 macrosatellite repeat array located at 4q35. Interestingly, D4Z4 deletion is not sufficient per se to cause FSHD. Moreover, the disease severity, its rate of progression and the distribution of muscle weakness display great variability even among close family relatives. Hence, additional genetic and epigenetic events appear to be required for FSHD pathogenesis. Indeed, recent findings suggest that virtually all levels of epigenetic regulation, from DNA methylation to higher order chromosomal architecture, exhibit alterations in the disease locus causing deregulation of 4q35 gene expression, ultimately leading to FSHD.
    Epigenomics 04/2010; 2(2):271-87. DOI:10.2217/epi.10.8 · 5.22 Impact Factor
Show more