Facioscapulohumeral muscular dystrophy (FSHD) was linked to contractions in the number of D4Z4 repeats on chromosome 4q35 two decades ago. These contractions do not completely remove or mutate any genes, and solving the central mystery of how they lead to FSHD has been the most critical need in the field since this genetic abnormality was discovered. Recent work provides hope that the pathogenic mechanisms are coming into focus. Several published studies, including ours, support an FSHD pathogenesis model involving over- expression of the D4Z4-localized DUX4 gene, which encodes a transcription factor. These findings have sharpened the focus of the FSHD field, and there is now growing momentum to understand DUX4 biology and the mechanisms by which it may contribute to FSHD development. In our initial work, we demonstrated the myopathic potential of DUX4 in animal muscle, and showed that DUX4 toxicity was dependent upon its ability to bind DNA and activate p53-dependent cell death pathways. In this proposal, we will test several hypotheses addressing the mechanistic role of DUX4 and the p53 pathway in FSHD pathogenesis. These studies will help define the pathogenic insults underlying FSHD, which is ultimately necessary for therapeutic development.

Public Health Relevance

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscle disorders. FSHD is currently untreatable, and a major reason for this is its underlying cause has been difficult to determine despite two decades'worth of research. In this proposal, we will build on our recently published studies supporting a role for the DUX4 gene in the development of FSHD. We hypothesize that DUX4 expression in FSHD causes programmed muscle cell death, and we will determine whether features of human FSHD are reproduced in mice expressing human DUX4 sequences. These studies may provide important data that will ultimately lead to treatments for FSHD.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Nuckolls, Glen H
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Nationwide Children's Hospital
United States
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Wallace, Lindsay M; Saad, Nizar Y; Pyne, Nettie K et al. (2018) Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD. Mol Ther Methods Clin Dev 8:121-130
Giesige, Carlee R; Wallace, Lindsay M; Heller, Kristin N et al. (2018) AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD. JCI Insight 3:
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