FSHD is an autosomal dominant, progressive neuromuscular disorder, with a prevalence of 1:20,000. FSHD genetic defect does not reside in any mutated genes. Its pathogenesis has been associated with deletion of 3.3 kb tandemly arrayed repetitive elements, named D4Z4, located at 4q35 region. Expression analysis to all known genes mapping at 4q35, revealed that ANT1, FRG1, and FRG2 genes were over-expressed in FSHD affected muscle. We discovered that D4Z4 contributes to gene silencing at 4q35 by specifically interacting with a transcriptional repressing complex. Based upon these results we proposed that deletion of D4Z4 elements leads to the inappropriate transcriptional derepression of 4q35 genes resulting in disease. To verify this model we generated transgenic mice over-expressing ANT1, FRG1, and FRG2. Interestingly, mice over-expressing FRG1 develop muscular dystrophy whose degree of severity correlates with the level of over-expression of the transgene. These observations support the pathogenic model proposed for FSHD and strongly indicate that FRG1 plays a pivotal role in FSHD pathogenesis. Additional studies are necessary to lay the basis of effective treatments for FSHD.
Our specific aims are: 1. To study the effect of FRG1 expression in normal physiology and disease related processes. 2. To generate and characterize transgenic animals over-expressing multiple 4q35 genes. 3. To develop potential therapeutic approaches for treating FSHD. At present, there is no effective treatment for people with FSHD. We studied human muscle tissues from normal individuals and from people with FSHD, and found that activity of three genes, ANT1, FRG1, FRG2, was elevated in the muscle from FSHD patients compared to that of other people. Studying mice in which each one of the three genes, ANT1, FRG1, FRG2, is overactive, we found that one of these genes, FRG1, causes muscular dystrophy when it is too active. This observation suggests that FRG1 is being responsible for the symptoms of FSHD. Therefore mice in which FRG1 is too active represent a useful model for studying FSHD onset and progression and can help to develop an effective treatment for FSHD. We anticipate that this study will lay the basis for a therapeutic intervention on FSHD.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Nuckolls, Glen H
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Sancisi, Valentina; Germinario, Elena; Esposito, Alessandra et al. (2014) Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1). Am J Physiol Regul Integr Comp Physiol 306:R124-37
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