Uncovering the cause of a Common Form of Muscular Dystrophy: FSH Society Funded Research Team Makes Second Critical Advance
SEATTLE – An international team of researchers led by an investigator from Fred Hutchinson Cancer Research Center has made a second critical advance in determining the cause of a common form of muscular dystrophy known as facioscapulohumeral dystrophy, or FSHD.
In August 2010 the group published a landmark study that established a new and unifying model for the cause of FSHD. The current work, published Oct. 28 in PLoS Genetics, shows that the disease is caused by the inefficient suppression of a gene that is normally expressed only in early development. The work will lead to new approaches for therapy and new insights into human evolution.
The disease-causing gene, called DUX4, previously had been thought to be a completely inactive gene in humans. DUX4 belongs to a special class of genes called retrogenes, which usually represent unused byproducts of evolution that have no remaining biological function, sometimes called “dead genes.”
In contrast, the researchers discovered that the DUX4 protein is abundantly expressed in human germ-line cells, the cells that form the sperm and eggs, which indicates a necessary function early in development. Normally, the DUX4 gene is suppressed in all other cells of the body. However, the mutation that causes FSHD makes this suppression less efficient.
“The result is that the DUX4 gene occasionally escapes the inefficient suppression and is expressed in some muscle cells, similar to the Old Faithfull geyser that is usually off but occasionally releases a burst of water,” said corresponding author Stephen Tapscott, M.D., Ph.D., a member of the Hutchinson Center’s Human Biology Division. “The occasional ‘bursts’ of DUX4 are thought to be toxic to the muscle cells, which leads to muscle cell death and the muscular dystrophy.”
Tapscott led the study in collaboration with Daniel Miller, M.D., Ph.D., at the University of Washington, and co-authors Silvere van der Maarel, Ph.D., and Rabi Tawil, M.D., at Leiden University Medical Center and the Fields Center for FSHD and Neuromuscular Research at the University of Rochester, respectively.
Previously, these same investigators had shown that the reason some people are protected from getting FSHD is that they have mutations in a region of DNA that is necessary to stabilize the DUX4 gene product. These new findings confirm the role of the DUX4 protein in FSHD and reveal a new mechanism of human disease caused by the inefficient suppression of a retrogene that has a role in early development. These findings will provide a focus for future development of therapies for FSHD.
There are broader implications of the new research for understanding human evolution as well. Maintenance of a functional retrogene in humans indicates that it provided some selective advantage during evolution.
“Since FSHD is characterized by excessively weak upper extremity muscles and facial muscles, we speculate that the DUX4 retrogene might have a normal role in causing the weaker and more expressive facial muscles in humans compared to non-human primates,” Tapscott said. “If this suggestion is correct, it means that FSHD is caused by increasing the normal role of DUX4 and causing a more extreme weakness of facial and upper extremity muscles. It also means that all humans have a little bit of FSHD and that this contributes to the evolution of these muscles.”
The researchers have an ongoing collaboration through a Hutchinson Center-based National Institutes of Health FSHD Program Project Grant, of which Tapscott is principal investigator.
“The progress was made possible by an unusual degree of collaboration and data-sharing among the individual groups,” Tapscott said.
Grants from the NIAMS and NINDS sections of the National Institutes of Health, the Friends of FSH Research, the Shaw Family Foundation and the Muscular Dystrophy Association also supported the work of Tapscott and colleagues at the Hutchinson Center.
Other funding for this study came from the Fields Center, the Netherlands Organization for Scientific Research, the Netherlands Genomic Initiative, a Marjorie Bronfman Fellowship grant from the FSH Society, the Centro Investigacion Biomedica en Red para Enfermedades Neurodegenerativas, the Basque Government and the Instituto Carlos III, ILUNDAIN Fundazioa.
See full article at PLoS Genetics by clicking HERE. To read PDF file ckck HERE.
PLoS Genet. 2010 Oct 28;6(10):e1001181.
Facioscapulohumeral Dystrophy: Incomplete Suppression of a Retrotransposed Gene
Lauren Snider1#, Linda N. Geng1#, Richard J. L. F. Lemmers2, Michael Kyba3, Carol B. Ware4, Angelique M. Nelson4, Rabi Tawil5, Galina N. Filippova6, Silvère M. van der Maarel2, Stephen J. Tapscott1,6*, Daniel G. Miller7
1 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 2 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands, 3 Lillehei Heart Institute and Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, United States of America, 4 Department of Comparative Medicine, University of Washington, Seattle, Washington, United States of America, 5 Department of Neurology, University of Rochester, Rochester, New York, United States of America, 6 Department of Neurology, University of Washington, Seattle, Washington, United States of America, 7 Department of Pediatrics, University of Washington, Seattle, Washington, United States of America
Abstract Top
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.
