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—Dr. Silvère van der Maarel
After their recent publication in Science, the same international research collaboration that includes research groups funded by the Friends of FSH Research has made further advancements in our understanding of the molecular cause of facioscapulohumeral dystrophy (FSHD). While their earlier work reported in Science provided genetic evidence that expression and stabilization of DUX4 is critically important for the development of FSHD, the recent report in PLoS Genetics provides an answer as to how a gene expressed at such low concentrations can be toxic to muscle. Low expression of DUX4 can either mean that all muscle nuclei express tiny amounts of the toxic DUX4 protein or that only few out of many nuclei express high levels of DUX4. In this report, the scientists provide compelling evidence for the latter scenario. This finding is important as it provides a model in which occasional bursts of DUX4 in muscle of patients with FSHD can explain the progressive nature of this disease. It also provides a clear target for the design of therapeutics for FSHD.
This study, published in PLoS Genetics, was led by Dr. Stephen Tapscott (Fred Hutchinson Cancer Research Center in Seattle) and Dr. Daniel Miller (University of Washington in Seattle), together with Dr. Silvère van der Maarel (Leiden University Medical Center) and Dr. Rabi Tawil (University of Rochester). This is the second report facilitated by the unprecedented degree of collaboration and data-sharing among the individual groups with support of the Fields Center for FSHD & Neuromuscular Research. These scientists first began sharing their expertise at yearly workshops sponsored by the Friends of FSH Research and the Shaw Family Foundation. In addition to sponsoring these opportunities to collaborate, Friends of FSHD Research and the Shaw Family foundation also funded research in the Tapscott, Miller and van der Maarel laboratories. By leveraging this support network, these researchers successfully received grant funding from the National Institutes of Health and the Muscular Dystrophy Association to continue their FSHD research studies.
Funding for this study came from NIAMS and NINDS sections of the National Institutes of Health, the Friends of FSH Research, the Shaw Family Foundation, the Fields Center for FSHD & Neuromuscular Research, the University of Washington and the Muscular Dystrophy Association.
See the previous related paper
Facioscapulohumeral Dystrophy: Incomplete Suppression of a Retrotransposed Gene
Lauren Snider1,•, Linda N Geng1,•, Richard JLF Lemmers3, Michael Kyba4, Carol B Ware5, Angelique M Nelson5, Rabi Tawil6, Galina N Filippova2, Silvère M van der Maarel3, Stephen J Tapscott1,2,8, Daniel G Miller7.
Each unit of the D4Z4 macrosatellite repeat contains a retrotransposed gene encoding the DUX4 double-homeobox transcription factor. Facioscapulohumeral dystrophy (FSHD) is caused by deletion of a subset of the D4Z4 units in the subtelomeric region of chromosome 4. Although it has been reported that the deletion of D4Z4 units induces the pathological expression of DUX4 mRNA, the association of DUX4 mRNA expression with FSHD has not been rigorously investigated, nor has any human tissue been identified that normally expresses DUX4 mRNA or protein. We show that FSHD muscle expresses a different splice form of DUX4 mRNA compared to control muscle. Control muscle produces low amounts of a splice form of DUX4 encoding only the amino-terminal portion of DUX4. FSHD muscle produces low amounts of a DUX4 mRNA that encodes the full-length DUX4 protein. The low abundance of full-length DUX4 mRNA in FSHD muscle cells represents a small subset of nuclei producing a relatively high abundance of DUX4 mRNA and protein. In contrast to control skeletal muscle and most other somatic tissues, full-length DUX4 transcript and protein is expressed at relatively abundant levels in human testis, most likely in the germ-line cells. Induced pluripotent (iPS) cells also express full-length DUX4 and differentiation of control iPS cells to embryoid bodies suppresses expression of full-length DUX4, whereas expression of full-length DUX4 persists in differentiated FSHD iPS cells. Together, these findings indicate that full-length DUX4 is normally expressed at specific developmental stages and is suppressed in most somatic tissues. The contraction of the D4Z4 repeat in FSHD results in a less efficient suppression of the full-length DUX4 mRNA in skeletal muscle cells. Therefore, FSHD represents the first human disease to be associated with the incomplete developmental silencing of a retrogene array normally expressed early in development.
Facioscapulohumeral muscular dystrophy is caused by the deletion of a subset of D4Z4 macrosatellite repeats on chromosome 4. Each repeat contains a retrogene encoding the double-homeobox factor DUX4. We show that this retrogene is normally expressed in human testis, most likely the germ-line cells, and pluripotent stem cells. DUX4 expression is epigenetically suppressed in differentiated tissues and the residual DUX4 transcripts are spliced to remove the carboxyterminal domain that has been associated with cell toxicity. In FSHD individuals, the expression of the full-length DUX4 transcript is not completely suppressed in skeletal muscle, and possibly other differentiated tissues, and results in a small percentage of cells expressing relatively abundant amounts of the full-length DUX4 mRNA and protein. We therefore propose that FSHD is caused by the inefficient developmental suppression of the DUX4 retrogene and that the residual expression of the full-length DUX4 in skeletal muscle is sufficient to cause the disease. Therefore, FSHD represents the first human disease to be associated with the incomplete developmental silencing of a retrogene array that is normally expressed early in development.
See PLoS Genetics article
See discussion of the article on PLoS Genetics by Christopher E. Pearson
See Daily News & Analysis article
See News-Medical.Net article
See Newswire release by Fred Hutchinson CRC