Published online before print December 6, 2006, doi:10.1212/01.wnl.0000251269.31442.d9)
NEUROLOGY 2007;68:569-577
© 2007 American Academy of Neurology
Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy
R. J. Osborne, PhD,
S. Welle, PhD,
S. L. Venance, MD, PhD,
C. A. Thornton, MD and
R. Tawil, MD
From the Departments of Neurology (R.J.O., C.A.T., R.T.), and Medicine (S.W.), University of Rochester School of Medicine and Dentistry, Rochester, NY; and the Department of Clinical Neurological Sciences (S.L.V.), London Health Sciences Centre, London, ON, Canada.
Address correspondence and reprint requests to Dr. Rabi Tawil, Neuromuscular Disease Center, Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elwood Avenue, Box 673, Rochester, NY 14642-8673; e-mail: rabi_tawil{at}urmc.rochester.edu
Background: Facioscapulohumeral muscular dystrophy (FSHD) is caused by deletions within a tandem array of D4Z4 repeats on chromosome 4q35. In addition to muscle degeneration, most patients with FSHD develop abnormalities of the retinal vasculature. Previous work has suggested that muscle degeneration in FSHD results from increased expression of genes proximal to the deletion, including FRG1.
Objectives: To reexamine this mechanism and identify pathways that are abnormally regulated early in the disease process.
Methods: We prospectively studied gene expression in skeletal muscle in patients with FSHD (n = 19) vs healthy individuals (n = 30) and patients with myotonic dystrophy type 1 (n = 12). We used oligonucleotide microarrays for global analysis of gene expression and reverse transcriptase-PCR (RT-PCR) to assess expression or alternative splicing for particular genes.
Results: Expression of FRG1 was not increased in patients with FSHD, either by microarray analysis or quantitative RT-PCR. Among genes on 4q35, only LRP2BP showed upregulation that was specific to FSHD. However, neither LRP2BP nor FRG1 showed imbalance of allelic expression by RT-PCR. After filtering out genes that showed similar dysregulation in other forms of muscular dystrophy, only 44 genes were specifically upregulated early in FSHD. Among these, 34 genes were characterized or partially characterized, of which 11 (32%) had a role in vascular smooth muscle or endothelial cells.
Conclusion: Expression of genes on chromosome 4q35 was normally regulated in the early stages of facioscapulohumeral muscular dystrophy. Our results support a possible link between muscular dystrophy and retinal vasculopathy in facioscapulohumeral muscular dystrophy.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the February 20 issue to find the title link for this article.
Editorial, see page 544
See also page 578
This article was previously published in electronic format as an Expedited E-pub on December 6, 2006, at www.neurology.com.
Supported by the University of Rochester Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center (NIH/NS48843), the Wayne C. Gorell Jr. Laboratory with support from the NIH (AR49077), the Muscular Dystrophy Association, the Saunders Family Neuromuscular Research Fund, and the University of Rochester Clinical Research Center (NIH RR00044). Patients were enrolled in the study with the assistance of the National Registry of Myotonic Dystrophy and Facioscapulohumeral Dystrophy Patients and Family Members (NIH AR02250).
Disclosure: The authors report no conflicts of interest.
Received June 30, 2006. Accepted in final form October 16, 2006.
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