FSHD: A Repeat Contraction Disease Finally Ready to Expand

PLoS Genetics: FSHD: A Repeat Contraction Disease Finally Ready to Expand (Our Understanding of Its Pathogenesis)

Christopher E. Pearson^1,2*

1 Program of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, 2 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

Facioscapulohumeral muscular dystrophy (FSHD), was one of the first diseases shown to be caused by an unstable repeat in the early 1990s along with spinal and bulbar muscular atrophy (SBMA), myotonic dystrophy (DM1), and fragile X mental retardation (FRAXA), where the latter three are caused by genetically expanding trinucleotide repeats [1]. However, FSHD differs considerably from the trinuclotide repeat diseases, as it is caused by a contraction of a macrosatellite (D4Z4 repeat, 3.3 kb/unit). Moreover, far less is understood about the pathogenic mechanism for FSHD, relative to SBMA, DM1, and FRAXA. This is not due to a shortage of experimental efforts, plausible hypotheses, or collaborative efforts towards understanding FSHD [2], [3]. The elucidation of FSHD is hampered by the size of the unstable repeat, its sequence complexity, the number of repeat units, and the presence of the repeat on Chromosomes 4 and 10, making analysis technically difficult. The difficulty is compounded further by the absence of an obvious gene, transcript, or protein in the unstable or proximal region; in fact, the D4Z4 repeats have been referred to as “junk” DNA or are thought to be a pseudogene, at best. As a result, FSHD has proved to be one of the most complex and challenging genetic diseases to even a glimpse an underlying pathogenic cause for FSHD. Several recent papers, including one in this issue of PLoS Genetics [4], have made significant advances that now permit us to expand our understanding of FSHD pathogenesis, a repeat contraction disease.

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Uncovering the Cause of a Common Form of Muscular Dystrophy: Research Team Makes Second Critical Advance | Science Magazine News

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, and through the Fields Center for FSHD and Neuromuscular Research, of which Tawil is the director.

"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.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.
Source: The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Fred Hutchinson Cancer Research Center.

Uncovering the cause of a common form of muscular dystrophy

Research team makes second critical advance

SEATTLE—Oct. 28, 2010

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 and through the Fields Center for FSHD and Neuromuscular Research, of which Tawil is the director.

“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.

Note for media only: To obtain a copy of the PLoS Genetics paper, “Facioscapulohumeral Dystrophy: Incomplete Suppression of a Retrotransposed Gene,” or to arrange an interview with Tapscott, please contact Kristen Woodward in Hutchinson Center media relations at 206-667-5095 or kwoodwar@fhcrc.org.

###

Kristen Woodward
Fred Hutchinson Cancer Research Center
(206) 667-5095
kwoodwar@fhcrc.org

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FSHD Muscular Dystrophy - Documentary

The challenge of unraveling the genetics of FSHD

Preliminary ACE-031 Results

Acceleron Presents Preliminary ACE-031 Results from a Phase 1 Multiple Ascending Dose Study in Healthy Volunteers

Acceleron Pharma, Inc., a biopharmaceutical company developing novel therapeutics that modulate the growth of cells and tissues including muscle, bone, fat, red blood cells and the vasculature, today announced preliminary results from a Phase 1b study to assess the safety, tolerability and pharmacodynamic (PD) activity of ACE-031 following multiple ascending doses in healthy postmenopausal volunteers. ACE-031 is an investigational protein therapeutic designed to build muscle and increase strength by blocking proteins that inhibit muscle growth. In the trial, ACE-031 was generally well-tolerated with rapid and sustained effects on muscle, bone and fat. Preliminary results from this randomized, placebo-controlled study were presented at the 15^th International Congress of the World Muscle Society in Kumamoto, Japan.

Read more: http://www.kansascity.com/2010/10/13/2307913/acceleron-presents-preliminary.html#ixzz12I8Xufqg

A Unifying Genetic Model for FSHD - Review

Faculty of 1000 Biology |
A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy.
By Dr. Jane Hewitt

This publication gives significant insight into the fascinating and unique molecular mechanism of facioscapulohumeral muscular dystrophy (FSHD). The causative mutation has been known for almost 20 years to be a deletion in a tandem DNA array (D4Z4) encoding a putative homeodomain protein (DUX4), but why the deletion results in FSHD has been unclear and hotly debated. D4Z4 deletions only cause FSHD if they occur on particular 4q haplotypes that are termed permissive. Now, Lemmers et al., using a combination of high resolution haplotyping and analysing patients with atypical but informative genetic architectures, provide a plausible and intriguing model for FSHD. They show that D4Z4 deletions allow inappropriate generation of a transcript (DUX4) from the distal D4Z4 repeat that utilises a non-canonical polyA signal in an adjacent stretch of beta-satellite DNA, stabilising the mRNA.

The FSHD mutation was first identified in 1992 as a deletion within the D4Z4 tandem DNA array at chromosome 4q35 {1}. This polymorphic array contains 12-150 copies of a 3.3kb DNA repeat in unaffected individuals; in FSHD patients, the number of repeat units is reduced to about 10 or fewer. Although the potential for this array to encode a homeodomain protein was recognised almost immediately {2}, it proved difficult to find evidence that a transcript or protein was produced. Consequently, many researchers proposed that the D4Z4 deletions altered the chromatin structure of this region, affecting the expression of genes proximal to the array. Although there were some data that supported this position effect model, many other studies failed to replicate these findings. Recently, several groups identified transcriptional activity from D4Z4 {3,4} and the DUX4 open reading frame was shown to be evolutionarily conserved {5}; D4Z4 has for several years been known not to be junk DNA or a dead gene. Together with data showing that only some 4q haplotypes are permissive for the disease {6}, these findings shifted focus back to a direct role for the D4Z4 repeat in FSHD. Epigenetic changes in D4Z4 chromatin that were specific for FSHD were recently identified {7}. Here, Lemmers et al. provide a model that is consistent with all these previous studies on D4Z4. Like any good paper, this one raises further questions. Lemmers et al. previously reported that one 4q haplotype (termed 4qA166) is non-permissive for FSHD {6}. Here, they do not report whether the polyA signal is absent in this non-permissive haplotype. A subset of FSHD patients (termed phenotypic FSHD or FSHD2) do not have D4Z4 deletions but do show similar epigenetic changes within the array. It will be important to test whether these patients also show inappropriate activation of DUX4 mRNA. Finally, this polyadenylation signal is not essential for normal DUX4 function since approximately 25% of the population is homozygous for 4qB haplotypes that lack this sequence. Therefore, the relationship between normal DUX4 function and FSHD remains to be resolved. NB - Jane Hewitt is an author on refs {1,2,5}.

References: {1} Wijmenga et al. Nature Genet 1992, 2:26-30 [PMID:1363881]. {2} Hewitt et al. Hum Mol Genet 1994, 3:1287-95 [PMID:7987304]. {3} Dixit et al. Proc Natl Acad Sci USA 2007, 104:18157-62 [PMID:17984056]. {4} Snider et al. Hum Mol Genet 2009, 18:2414-30 [PMID:19359275]. {5} Clapp et al. Am J Hum Genet 2007, 81:264-79 [PMID:17668377]. {6} Lemmers et al. Am J Hum Genet 2007, 81:884-94 [PMID:17924332]. {7} Zeng et al. PLoS Genet 2009, 5:e1000559 [PMID:19593370].

Multi-National Research - Making Strides for FSHD Research

Two genetic changes needed to cause FSHD

Facioscapulohumeral muscular dystrophy (FSHD) requires the presence of not one but two genetic changes, both on chromosome 4, MDA-supported scientists have found.
MDA grantee Silvère van der Maarel at Leiden (Netherlands) University Medical Center coordinated the multinational study team, which announced its findings online Aug. 19, 2010, in the journal Science.

Two genetic changes — a contracted segment of DNA on chromosome 4, and a "permissive" signal near it on the same chromosome — are necessary to complete the FSHD puzzle.

The investigators found that two genetic requirements, located near each other on the tip of chromosome 4, must be combined for FSHD symptoms to appear. One requirement is a deletion of some of the DNA in a region of chromosome 4 called D4Z4. Its contribution to FSHD has been recognized for many years. The second requirement, newly recognized, is a particular variant of DNA further toward the tip of chromosome 4 than the D4Z4 region.

The variant contains a “polyadenylation” signal, which stabilizes otherwise fragile genetic instructions called RNA transcripts, after they’re synthesized from DNA (genes).

The presence of a polyadenylation signal makes it more likely that genetic instructions will stick around long enough to be translated into proteins, the final product of DNA and RNA instructions. In this case, the signal appears to make it possible for one or more potentially toxic proteins to be produced.

More than 300 people with FSHD and more than 2,000 people without the disease were studied. All the people with FSHD had a contracted D4Z4 region on chromosome 4 and at least one of three “permissive” DNA sequences further out toward the tip of the same chromosome.

Among the more than 2,000 people without any FSHD symptoms that the investigators studied, some had contracted D4Z4 regions on chromosome 4. However, they all had “nonpermissive” signals further out on the chromosome.
Without a “permissive” polyadenylation signal, the researchers believe, genetic instructions (RNA) from the D4Z4 region don’t last long enough to cause muscle-cell damage.

The new findings will make it easier to diagnose FSHD in someone with symptoms and predict who will develop the disease among those without symptoms.
Once the identities of the toxic proteins or RNA instructions are established, therapeutic strategies to block them could potentially be developed.

(Part of the multi-national team responsible for these recent findings include Friends of FSH Research supported Seattle researchers - Thanks to everyone for your donations that made this work possible)