Major breakthrough in muscular dystrophy research

Major breakthrough in muscular dystrophy research

It’s often said in research circles that many pairs of eyes are better than just one set when it comes to looking at complex problems.

And at the Hutchinson Center, that kind of collaboration reaches across the globe—often leading to groundbreaking results. Such is the case with the latest news on muscular dystrophy, a disease that has vexed the scientific community for decades.

Researchers have known for 20 years that a genetic mutation is present in people with a common form of muscular dystrophy known as facioscapulohumeral dystrophy, or FSHD, a condition characterized by progressive wasting of muscles in the upper body.

People affected by FSHD share a gene called DUX4 that produces a protein toxic to muscle cells. However, researchers had not been able to explain what caused DUX4 to mutate and create the toxic protein.

Now, they think they have found the key that turns the process on. This summer, an international team—with a Hutchinson Center researcher in a pivotal role—identified a DNA sequence that causes DUX4 to be more active. They now believe that two distinct genetic changes on chromosome 4 must be present to cause FSHD.

“In contrast to most genetic diseases, knowledge of the genetic mutation did not explain the cause of the disease,” said Dr. Stephen Tapscott, an expert in neurogenetics and neuromuscular disease at the Hutchinson Center, and one of the co-authors of the study.

Thanks to these findings, researchers hope it will become easier to diagnose the disease and predict in people showing no symptoms, who will develop it. Currently, FSHD affects 300,000 people worldwide. The latest research also is likely to open the door to new therapies.

“The progress was made possible by an unusual degree of collaboration and data-sharing among the individual groups,” said Tapscott, who was one of several researchers who participated in the study.

(note: Friends of FSH Research launched Dr. Tapscott and the work at Fred Hutch through a pilot grant given in 2006 and other supportive funding through 2010)

FSHD: copy number variations on the theme of muscular dystrophy — JCB

FSHD: Copy Number Variations on the Theme of Muscular Dystrophy

• JCB Home, Dec. 13
  

1. Daphne Selvaggia Cabianca1,2 and
2. Davide Gabellini2

In humans, copy number variations (CNVs) are a common source of phenotypic diversity and disease susceptibility. Facioscapulohumeral muscular dystrophy (FSHD) is an important genetic disease caused by CNVs. It is an autosomal-dominant myopathy caused by a reduction in the copy number of the D4Z4 macrosatellite repeat located at chromosome 4q35. Interestingly, the reduction of D4Z4 copy number is not sufficient by itself to cause FSHD. A number of epigenetic events appear to affect the severity of the disease, its rate of progression, and the distribution of muscle weakness. Indeed, recent findings suggest that virtually all levels of epigenetic regulation, from DNA methylation to higher order chromosomal architecture, are altered at the disease locus, causing the de-regulation of 4q35 gene expression and ultimately FSHD.

(click on title link to read entire report)

Conclusions

Recent studies suggest that copy number variations (CNVs) are important for human phenotypic diversity and disease susceptibility. DNA repeats account for 55% of the human genome and a significant fraction of CNVs.

FSHD is an important pathology caused by CNVs of D4Z4 repeats. It is an extremely complicated and fascinating disease, and research into this topic is revealing much about the functional organization of our genome.

An increasing amount of evidence suggests that the 4q35 macrosatellite repeat D4Z4 plays a crucial role in the chromosomal organization of the FSHD region. There is a general consensus that the D4Z4 deletion in FSHD leads to epigenetic alterations that affect the expression profiles of genes within the FSHD region. Unfortunately, despite considerable effort, almost 20 years after the identification of the genetic defect underlying the disease, the causative FSHD gene(s) remains unknown, and no effective treatments for FSHD are currently available.

The heterogeneity in disease manifestation probably reflects heterogeneity in gene expression in FSHD. An interesting possibility, therefore, is that the complexity of FSHD could be explained by considering it to be a contiguous gene syndrome, where the epigenetic alteration of DUX4, FRG1, and other potential genes collaborate to determine the final phenotype. Finally, because DUX4 behaves as a transcriptional activator (Dixit et al., 2007), it could play a direct role in transcriptional overexpression of the other 4q35 genes, providing a unifying model for the molecular mechanism of the disease.

Ryan Levinson - Can’t choose what happens to you, only how you respond to it.”

Read article about Ryan Levison - FSHD Athlete

New FSHD Findings - Summary

(This is a nice summary of recent research findings - from the UK Muscular dystrophy newsletter - you can read more about this work, and the work done by researchers funded by Friends of FSH Research on our website)

Monday 22 November 2010

New research increases understanding of facioscapulohumeral muscular dystrophy.

An international group of scientists has shed further light on the molecular mechanism that causes facioscapulohumeral muscular dystrophy (FSH). Recent research has provided evidence that the piece of DNA that is changed in people with FSH contains a gene called DUX4, the function of which is so far unknown. The results of this new research provide evidence that the DUX4 gene can produce different versions of DUX4 protein and that the deletion in patients with FSH leads to the production of a version that is toxic for muscle cells. These important findings will be vital to bring scientists closer to developing a treatment.

FSH is caused by changes to a region of DNA on chromosome 4 called D4Z4 that has the same piece of DNA code repeated many times. In healthy individuals the number of repeats varies between 11 and 100. People with FSH have less than 11 repeats.  Recent research demonstrated that the repeated section of DNA contains a gene called DUX4. The reduction in the number of repeats on D4Z4 to less than 11 changes the way this piece of DNA is folded (this is known as the chromatin structure). This exposes the DNA code to be read by the cell, like opening a book. They also showed that an activation signal also needs to be present next to the DUX4 gene. In other words, the book needs to be open and the light switched on before you can read it. Read more about these previous results.
But this is not the whole story and this new research builds on these previous findings to further clarify the mechanism causing FSH.

Contents

• What does the research show?
• What does this mean for patients?
• Further information and links
  

What does the research show?

The researchers analysed tissue samples to find out more about the protein that is produced from the instructions in the DUX4 gene. They found that the DUX4 protein was made in two forms - a full-length and a shortened version. The full-length protein could not be found in the muscles of people unaffected by FSH, instead the shorter version of the protein was found. Of the tissues they examined, the full-length version was only present in testes. However, muscle samples from people with FSH were found to be producing the full length DUX4 protein. It should be noted that in people with FSH only a very small proportion of muscle cells produce the longer version of the protein.
These results suggest that muscle cells actively read the DUX4 gene but the protein is processed differently in people with FSH. This leads to the production of the full-length version that is not found in the muscle cells of people unaffected with FSH. It is thought that the way the DNA is folded may be determining this. In healthy cells the DNA is more tightly coiled and this may be influencing the cell to "cut out" parts of the DUX4 protein to create the shortened version. The DNA in the FSH muscle is much more loosely folded, due to the smaller number of repeats, and so this signal to "cut out" part of the protein is missing.
The researchers also analysed "induced pluripotent stem cells" (iPS). These are made in the laboratory by reprogramming cells that already have a dedicated function, such as skin cells, so that they become stem cells. iPS cells are a useful tool for stem cell research and can be used to model disease processes. When researchers looked at iPS cells made from skin they found that they produced the full-length DUX4 protein which did not seem to be toxic for this cell type.
The researchers have suggested that the fact that the full-length version of the DUX4 protein is produced only in stem cells and testicular tissue might mean that it has a possible role during early development. In adult tissue, especially in muscle, the production of the full-length protein is switched off and the shorter version is produced. The changes in the DNA in people with FSH somehow have the effect that this switch is not happening. The muscle cells keep on making the full-length DUX4 protein that becomes toxic to the cells, inducing muscle damage.

What does this mean for patients?

This research represents a big step forward in our understanding of what causes FSH, something that has prevented scientists moving forward to develop potential therapies. These new results will allow researchers to further clarify the role of the DUX4 gene and protein in the development of the condition.
It is still not fully understood what the function the DUX4 protein is and why the full-length DUX4 protein appears to be toxic to the muscle and researchers will continue to investigate this. This current piece of research and the other recent findings about FSH have however, highlighted a target which researchers can now take advantage of to potentially start developing a therapy for this condition.

Inflammatory Role - Impacting FSHD Muscle Cells

J Clin Immunol. 2010 Nov 10. [Epub ahead of print]

CD8(+) T Cells in Facioscapulohumeral Muscular Dystrophy Patients with Inflammatory Features at Muscle MRI.

Frisullo G, Frusciante R, Nociti V, Tasca G, Renna R, Iorio R, Patanella AK, Iannaccone E, Marti A, Rossi M, Bianco A, Monforte M, Tonali PA, Mirabella M, Batocchi AP, Ricci E.

Institute of Neurology, Department of Neurosciences, Catholic University of Rome, largo Gemelli 8, 00168, Rome, Italy.

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disease, and although strongly suggested, a contribution of inflammation to its pathogenesis has never been demonstrated. In FSHD patients, we found by immunohistochemistry inflammatory infiltrates mainly composed by CD8(+) T cells in muscles showing hyperintensity features on T2-weighted short tau inversion recovery magnetic resonance imaging (T2-STIR-MRI) sequences. Therefore, we evaluated the presence of circulating activated immune cells and the production of cytokines in patients with or without muscles showing hyperintensity features on T2-STIR-MRI sequences and from controls. FSHD patients displaying hyperintensity features in one or more muscles showed higher CD8(+)pSTAT1(+), CD8(+)T-bet(+) T cells and CD14(+)pSTAT1(+), CD14(+)T-bet(+) cells percentages and IL12p40, IFNγ and TNFα levels than patients without muscles displaying hyperintense features and controls. Moreover, the percentages of CD8(+)pSTAT1(+), CD8(+)T-bet(+) and CD14(+)pSTAT1(+) cells correlated with the proportion of muscles displaying hyperintensity features at T2-STIR sequences. These data indicate that circulating activated immune cells, mainly CD8(+) T cells, may favour FSHD progression by promoting active phases of muscle inflammation.

PMID: 21063901 [PubMed - as supplied by publisher]

Dave Matthews & Tim Reynolds - Singing for Charity

Dave Matthews and Tim Reynolds will perform two unprecedented special benefit concerts on December 6th and 7th at Seattle’s McCaw Hall.  One hundred percent of the proceeds from these two shows will benefit charities selected by each ticket purchaser. 

Here’s how this works:

For each ticket you purchase for $135 for either show, you will receive a unique code worth $150 that you may use to direct a donation to any charity of your choosing on JustGive.org (a nonprofit organization that connects people to over 1.8 million charities).



Pacific Northwest Friends of FSH Research
Kirkland, WA 98033
Tax ID: 86-1108537

Have fun giving with your fellow concertgoers.  Consider making a collective impact by encouraging your neighbors and friends to all choose Friends of FSH Research!

Your directed donation is funded by Dave Matthews and a generous supporter.

100% of the proceeds will be donated the charity selected by the ticket purchasers.

Bottom line… See a great show while helping fund FSH Research!  THANKS!

Accessibility on Melbourne's trams - Thanks Ray!

Friends of FSH Research - An international research consortium shows that FSHD muscle nuclei are poised for expression of the toxic DUX4 protein

Friends of FSH Research - An international research consortium shows that FSHD muscle nuclei are poised for expression of the toxic DUX4 protein

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.

(read complete article on our website - Please donate to help us push this work toward a cure, thank you)

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.

(Click link to read entire article)

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

Fred Hutchinson Cancer Research Center
1100 Fairview Ave. N. PO Box 19024 Seattle, WA 98109
©2010 Fred Hutchinson Cancer Research Center, a 501(c)(3) nonprofit organization.
Terms of Use & Privacy Policy.

CenterNetCheck E-mail

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)

Running for FSHD Research

Invest in Others - BOSTON, July 28 /PRNewswire/ --

Runner - Andrew Prentice - Runs For FSH Research

BOSTON, July 28 /PRNewswire/ -- The Invest in Others Charitable Foundation, Inc., a public charity that supports the philanthropic and volunteer efforts of financial advisors across the country, today announced it has contributed $30,000 to Pine Street Inn through its Second Annual 5K Run/Walk event in Boston on Wednesday, July 28, 2010. Founded and based in Boston, Pine Street Inn is a charity committed to ending homelessness in the organization's home town. The donation will be directed towards Pine Street Inn's new Hartford Street Project, a 16-unit supportive housing program for homeless U.S. veterans that Pine Street Inn is preparing to open in the fall of 2010.

Following the Run/Walk, Invest in Others also awarded the top three male and female financial advisor finishers with a generous donation to the charity of their choice. This year's honorees included:

• Andrew Prentice of Bliss Investments in Olympia, WA; first place male financial advisor; benefiting Friends of FSH Research

Read more about this run at http://www.prnewswire.com/news-releases/invest-in-others-charitable-foundation-donates-30000-to-pine-street-inn-through-second-annual-5k-runwalk-in-boston-99470529.html

New Report Regarding Fascioscapulohumeral Dystrophy

Fascioscapulohumeral Dyst... : Neurology Today (to see entire article)

Neurology Today:

16 September 2010 - Volume 10 - Issue 18 - p 15

Although questions remain, the discovery, reported online in Science on Aug. 19, points the way toward an effective treatment for FSHD, which produces progressive wasting of muscles in the upper body.

“I don't think the importance of this can be over-emphasized,” said John Porter, PhD, program director of Neuromuscular Disease at the Neurogenetics Cluster and the NINDS Office of Translational Research, who was not involved with the study. “Without a mechanistic model that provides a hypothesis about the pathogenesis of a disease, researchers have difficulty getting grants. Grant applications have to be supported by a conceptual framework, and this provides a huge building block.”

(read entire report at Neurology Today)

September is Muscular Dystrophy Awareness Month

TORONTO, ONTARIO-- Sept. 1, 2010 - Keith Martin is a typical young adult in many ways: he's an avid Habs fan, and enjoys travelling and hanging out with friends. Keith is also a champion.

In 2005, at the age of 20, Keith was diagnosed with Facioscapulohumeral Dystrophy (FSHD). Three years later, in 2008, Keith and four friends cycled across Canada raising over $190,000 for Muscular Dystrophy Canada. Along the way, Keith inspired a nation to turn ideas into action.

"It's been a challenge overcoming the psychological effects of not having my body perform the way I feel it should. The sports I love have become harder and everyday tasks a little more difficult. I've gotten used to it, but I always notice it, and the adjustment is tough," says Keith about his diagnosis.

It's 2010 and Keith Martin's life is full. He graduated from the University of British Columbia in the spring, and is currently working in Montreal and looking forward to travelling the world.

FSHD is just one of more than 100 neuromuscular disorders. Each form is caused by an error in a specific gene related to muscle function. The symptoms of a neuromuscular disease vary according to the condition and may be mild, moderate or life-threatening. For some the disorder is fatal at a young age. No matter what the severity, entire families are affected. There is currently no cure. It is estimated that more than 50,000 Canadians are affected by a neuromuscular disorder.

Sensing a Breakthrough / Research News / News

Sensing a Breakthrough
Aug 17 2010

When researchers pinpointed the genetic mutation that leads to the disease known as facioscapulohumeral dystrophy (FSHD) in 1992, hopes rose that the discovery not only would result in better treatments but also eventually a cure for the disease.

"It will take a worldwide effort to solve this disease and the Fields Center wants to be a big part of the effort," said van der Maarel. "I am always cautious about making predictions for the future so not to mislead patients. What we would consider major breakthroughs likely will take years before it makes a difference to the patient. But yes, we are close to breakthrough and I am looking forward to the coming years in the Fields Center."

Tapscott also avoids predictions, but like Tawil and van der Maarel, he is optimistic.

"I do not think about this in terms of a breakthrough but rather in terms of steady progress," Tapscott said.

(read entire article)

Media-Newswire.com - Press Release Distribution - PR Agency

Nearly two decades after they identified the specific genetic flaw that causes a common type of muscular dystrophy, scientists believe they have figured out how that flaw brings about the disease.

The research was led by genetics researchers at the University of Leiden in the Netherlands, working together with scientists at the University of Rochester Medical Center, the Fred Hutchinson Cancer Research Center in Seattle, and other investigators. The research was funded by several organizations, including the Fields Center for FSHD and Neuromuscular Research, based at Rochester and at Leiden.

“It is amazing to realize that a long and frustrating journey of almost two decades now culminates in the identification of a single small DNA variant that differs between patients and people without the disease. We finally have a target that we can go after,” said Silvère van der Maarel, Ph.D., professor of medical epigenetics at Leiden and the corresponding author of the paper. Working closely with van der Maarel was the first author of the paper, Richard Lemmers of Leiden.

(read the complete article to learn more)

Zombie DNA linked to muscular dystrophy | The Cavalier Daily

The Cavalier Daily

By Aradhya Nigam on August 25, 2010

Out of the entire human genome, only 2 percent is known to code for functional genes. The remaining 98 percent — known as “junk DNA.” — has generally been thought to be unused by the body. A study recently published in “Science,” however, has shown that certain sequences of junk DNA may have the ability to come back to life. This movie-like “Zombie DNA” has severe — and, perhaps, frightening — implications, as researchers have discovered a particular set of junk DNA that, once active, causes facioscapulohumeral muscular dystrophy, or FSHD, an inherited disease that causes weakening of the muscles of the face and shoulder. The study pinpointed a repeating set of “zombie DNA,” with a certain mutation causing it to become activated. Researchers are now looking for different treatments to avoid activating the set of DNA, thwarting cases of FSHD. Researchers are keen to continue “zombie” DNA research, as its success with explaining FSHD will hopefully help find treatments to other diseases as well.

—compiled by Aradhya Nigam

It is amazing that a form of muscular dystrophy rarely heard about & more rarely written about has been front page news around the world and on the net for the past week. Hopefully this notice will help us raise the monies needed to move this research to the much needed treatment. Friends of FSH Research is proud to have played a small role in this scientific breakthrough, funding Stephen Tapscott and other FSH scientists in the Seattle area since 2005.

FHCRC & UW Researchers Participate in Muscular Dystrophy Gene Discovery

FHCRC & UW Researchers Participate in Muscular Dystrophy Gene Discovery

By Michael van Baker

Editor

Seattle/LocalHealthGuide has a story on the intercontinental team who have discovered the genetic link to a form of muscular dystrophy. Their paper, published in Science, details how expression of the DUX4 homeobox gene by an otherwise harmless stretch of "junk DNA" results in facioscapulohumeral muscular dystrophy (FSHD).

They're hypothesizing that the DUX4 protein is at some level toxic to muscle cell development, which results in FSHD's "weakness and wasting" of muscles in the face, shoulders, and upper arms--which can later reach the abdomen and hips. Eventually, it could be possible to medically disrupt the protein-encoding process--but for now identifying the protein in a lab's controlled conditions and in the body are two very different things.

(read more about the work at the Hutch and our researchers)

The curious genetics behind a form of muscular dystrophy | Seattle/LocalHealthGuide

Dr Tapscott - Fred Hutchinson Research Center - A Friends of FSH Research Grant Recipient

A scientific team that included researchers from Europe, the University of Rochester and Seattle has worked out how a curious genetic mutation may cause a common form of muscular dystrophy.

People with the condition, called facioscapulohumeral muscular dystrophy or FSHD, develop muscle weakness starting in face, shoulders and upper arms.

The weakness tends to appear when a person reaches his or her teens, grows more severe with time and can eventually spread to other muscle groups. Severity can range from mild to disabling.

The findings of the new study may someday lead to a treatment for the disease.

Silvère M. van der Maarel, professor of medical epidgenetics at Leiden University Medical Center led the study in collaboration with Dr. Rabi Tawil, M.D. of the University of Rochester Medical Center and Dr. Stephen Tapscott of the Division of Human Biology at the Fred Hutchinson Cancer Research Center. Dr. Daniel Miller of the University of Washington was also on the research team.

The search for the gene

Dr. Stephen Tapscott

Early genetic studies indicated that the gene causing FSHD was located at the end of chromosome 4. But it was not clear exactly where the gene was.

One area of interest was a structure at the end of the chromosome called a macrosatellite repeat array. These arrays are composed of the same sequence of DNA repeated over and over again.

Such arrays occur commonly in our chromosomes, but are usually inactive.

(to learn more, read this article)

Cause of FSHD muscle disease discovered - News - News & Events

FSHD Explained

Cause of FSHD muscle disease discovered

Researchers have known for some time that patients with the hereditary muscle disease FSHD lack part of chromosome 4. But there was uncertainty about how this leads to loss of muscle tissue. Researchers at the Leiden University Medical Center (LUMC) describe in an article in Science dated 19 August how the muscle damage comes about.

(here is a clear explanation for recent discoveries)

Research Moving Forward - Treatment Development Next

Facioscapulohumeral dystrophy (FSHD) gene findings may help scientists find a cure for muscular dystrophy

Findings may help scientists find a cure for muscular dystrophy

After 20 years, researchers have discovered how a flawed gene can cause this incurable condition

By Tara Foss
WebMD Health News

Reviewed by Dr Rob Hicks

20^th August – Researchers from Europe and the US have found the specific DNA flaw in genes that causes people to have facioscapulohumeral dystrophy (FSHD). The defective gene produces a protein, called DUX4, that is toxic to muscles. It is this activity that is the key to whether people have FSHD or not.
The paper is published in the journal Science and is the result of a close collaboration between researchers from the Netherlands, France, Spain and the US.
"It is amazing to realise that a long and frustrating journey of almost two decades now culminates in the identification of a single small DNA variant that differs between patients and people without the disease. We finally have a target that we can go after," says Dr Silvère van der Maarel, one of the paper’s authors and professor of medical genetics at the University of Leiden in the Netherlands.


(read the whole article)

International Research Team Closes In On Cause of Common Form of Muscular Dystrophy - AlphaTrade Finance

International Research Team Closes In On Cause of Common Form of Muscular Dystrophy

SEATTLE, Aug. 20 /PRNewswire/ -- An international team of researchers that includes investigators from Fred Hutchinson Cancer Research Center has made a critical advance in determining the cause of a common form of muscular dystrophy known as facioscapulohumeral dystrophy, or FSHD.

They have identified a DNA sequence in individuals with FSHD that causes a gene called DUX4 to be more active. Previous work from this research team and others has shown that this gene produces a protein that is toxic to muscle cells, and the current study indicates that it is likely to be key to developing FSHD. This finding points to potential new drug targets for treating - or potentially curing - FSHD, a progressive condition characterized by progressive wasting of muscles in the upper body.

The findings, published in the Aug. 20 issue of Science, shed new light on how a genetic mutation identified nearly 20 years ago causes the disease. The mutation is associated with the majority of FSHD cases, which affects some 300,000 people worldwide.

Researchers at the University of Leiden in the Netherlands led the study in collaboration with co-authors Stephen Tapscott, M.D., Ph.D., at the Hutchinson Center; Dan Miller, M.D., Ph.D., at the University of Washington; and Rabi Tawil, M.D., at the University of Rochester Medical Center, among others.

(read entire story at PRNewswire)

Scientists link a reawakened gene to muscular dystrophy - The Boston Globe

Scientists link a reawakened gene to muscular dystrophy - The Boston Globe


By Gina Kolata
New York Times / August 20, 2010


NEW YORK — Identifying a new disease mechanism, geneticists have found that the reawakening of a gene in a stretch of seemingly useless, or junk, DNA causes a common form of muscular dystrophy.

It is almost certain, specialists say, that other diseases will be found to have similar causes. The discovery also points the way, they say, toward new research on treatment of this disease.

The human genome is riddled with so-called dead genes that have not been active for ages, part of a vast amount of the genome that has no known function. But this is the first time, geneticists say, that they have seen a dead gene come back to life and cause a disease.

The disease, facioscapulohumeral muscular dystrophy, or FSHD, was known to be inherited in a simple pattern. But before this research, reported online yesterday in Science by an international group of researchers, its cause was poorly understood.

The culprit gene is part of what has been called junk DNA, regions whose function, if any, is largely unknown. In this case, the gene had seemed permanently disabled.

FSHD affects about 1 in 20,000 people, causing a progressive weakening of muscles in the upper arms, around the shoulder blades, and in the face — people who have the disease cannot smile. It is a dominant genetic disease. If a parent has the gene mutation that causes it, each child has a 50 percent chance of getting it, too. And anyone who inherits the gene is certain to get the disease.

About two decades ago, geneticists zeroed in on the region of the genome that seemed to be the offender: the tip of the longer arm of chromosome 4, which was made up of a chain of repeated copies of a dead gene. The dead gene was also repeated on chromosome 10, but that area of repeats seemed innocuous, unrelated to the disease. Only chromosome 4 was a problem.

The more they looked at that region of chromosome 4, the more puzzling it was. No one whose dead gene was repeated more than 10 times ever got FSHD.

Researchers say those extra copies change the chromosome’s structure, shutting off the region.
© Copyright 2010 Globe Newspaper Company.

An International Collaboration Identifies a Region of DNA

An international collaboration identifies a region of DNA necessary for FSHD and focuses attention on DUX4 as the cause of muscle deterioration

            An international research collaboration that includes research groups funded by the Friends of FSH Research has made a critical advance in determining the cause of facioscapulohumeral dystrophy (FSHD).  The mutation that causes the majority of FSHD cases was identified almost two decades ago but, in contrast to most genetic diseases, knowledge of the genetic mutation did not explain the cause of the disease.  Although many different models and hypotheses were proposed for how the FSHD mutation might cause the disease, none had sufficient experimental support to attain legitimacy, which resulted in controversy and slow progress in FSHD research. The recent publication in Science magazine focuses research on a single and testable hypothesis. Their work identified a DNA variation (polymorphism) necessary for FSHD that occurs outside the mutation region and is necessary for FSHD.  This DNA sequence in individuals susceptible to FSHD acts to stabilize the product of the DUX4 gene, whereas individuals not susceptible to FSHD have a different DNA sequence that does not stabilize DUX4.  This finding provides a new and unifying model for FSHD because it focuses studies on determining whether the DUX4 protein causes FSHD, as indicated by this group’s genetic analysis. 

            This study, published in Science magazine, was led by Dr. Silvere van der Maarel at the Leiden University Medical Center, together with Dr. Rabi Tawil at the University of Rochester, Dr. Stephen Tapscott at the Fred Hutchinson Cancer Research Center in Seattle, and Dr. Dan Miller at the University of Washington in Seattle. Rapid progress was made possible by an unusual degree of collaboration and data-sharing among the individual groups at yearly workshops sponsored by the Friends of FSH research.  The Friends of FSH Research, as well as the Shaw Family Foundation, sponsored yearly workshops that brought these collaborators together to share their research and also funded research in the laboratories of two of the groups (Dr. Stephen Tapscott at the Fred Hutchinson Research Center and Dr. Daniel Miller at the University of Washington). The initial progress supported by the Friends of FSH Research resulted in successful grant applications to the National Institutes of Health to continue their FSHD research studies.

Scientists Pinpoint Earliest Steps of Common Form of Muscular Dystrophy -- LEIDEN, The Netherlands, Aug. 19 /PRNewswire-USNewswire/ --

Scientists Pinpoint Earliest Steps of Common Form of Muscular Dystrophy --
LEIDEN, The Netherlands, Aug. 19 /PRNewswire-USNewswire/ --

LEIDEN, The Netherlands, Aug. 19 /PRNewswire-USNewswire/ -- Nearly two decades after they identified the specific genetic flaw that causes a common type of muscular dystrophy, scientists believe they have figured out how that flaw brings about the disease. The finding by an international team of researchers settles a longstanding question about the roots of facioscapulohumeral muscular dystrophy or FSHD. The work is published in the August 20 issue of Science.

Read the complete article for more details.

Friends of FSH Research has been very pleased to have worked with S. Tapscott since 2006.

Junk DNA Can Revive and Cause Disease, Study Finds - NYTimes.com

Junk DNA Can Revive and Cause Disease, Study Finds

The human genome is riddled with dead genes, fossils of a sort, dating back hundreds of thousands of years — the genome’s equivalent of an attic full of broken and useless junk.........

And the more they looked at that region of chromosome 4, the more puzzling it was. No one whose dead gene was repeated more than 10 times ever got FSHD. But only some people with fewer than 10 copies got the disease.

A group of researchers in the Netherlands and the United States had a meeting about five years ago to try to figure it out, and began collaborating. “We kept meeting here, year after year,” said Dr. Stephen J. Tapscott, a neurology professor at the University of Washington.

As they studied the repeated, but dead, gene, Dr. Tapscott and his colleagues realized that it was not completely inactive. It is always transcribed — copied by the cell as a first step to making a protein. But the transcriptions were faulty, disintegrating right away. They were missing a crucial section, called a poly (A) sequence, needed to stabilize them......

Thrilled to have the researcher we first funded in 2006 be recognized for this important work in a national publication - hopefully the awareness of FSHD and the importance of this research will be recognized.

FSHD Muscular Dystrophy Research Moving Forward

International research team closes in on cause of common form of muscular dystrophy

International research team closes in on cause of common form of muscular dystrophy

SEATTLE – An international team of researchers that includes investigators from Fred Hutchinson Cancer Research Center has made a critical advance in determining the cause of a common form of muscular dystrophy known as facioscapulohumeral dystrophy, or FSHD.
They have identified a DNA sequence in individuals with FSHD that causes a gene called DUX4 to be more active. Previous work from this research team and others has shown that this gene produces a protein that is toxic to muscle cells, and the current study indicates that it is likely to be key to developing FSHD. This finding points to potential new drug targets for treating – or potentially curing – FSHD, a progressive condition characterized by progressive wasting of muscles in the upper body.
The findings, published in the Aug. 20 issue of Science, shed new light on how a genetic mutation identified nearly 20 years ago causes the disease. The mutation is associated with the majority of FSHD cases, which affects some 300,000 people worldwide.
Researchers at the University of Leiden in the Netherlands led the study in collaboration with co-authors Stephen Tapscott, M.D., Ph.D., at the Hutchinson Center; Dan Miller, M.D., Ph.D., at the University of Washington; and Rabi Tawil, M.D., at the University of Rochester Medical Center, among others.
"In contrast to most genetic diseases, knowledge of the genetic mutation did not explain the cause of the disease," said Tapscott, a member of the Human Biology Division at the Hutchinson Center and an expert in neurogenetics and neuromuscular disease. "Although many different models and hypotheses were proposed for how the FSHD mutation might cause the disease, none had sufficient experimental support to attain legitimacy, which resulted in controversy and slow progress in FSHD research. These new findings provide a single, testable hypothesis," Tapscott said.
The research group identified a DNA variation, or polymorphism, necessary for FSHD that occurs near the mutation region on chromosome 4 that was discovered nearly two decades ago. In those susceptible to this form of muscular dystrophy, this DNA mutation stabilizes the product of the DUX4 gene and thus causes the gene to be more active.
"This provides a new and unifying model for FSHD because it will focus future research on determining whether the DUX4 protein causes FSHD, as indicated by our consortium's genetic analysis," Tapscott said.
Corresponding author Silvere van der Maarel, Ph.D., professor of medical epigenetics in the Department of Human Genetics at Leiden University Medical Center in the Netherlands, led the study in collaboration with Tapscott and Tawil, who is a professor of neurology and director of the Fields Center for FSHD and Neuromuscular Research, which is based at the University of Rochester and at the University of Leiden.
These researchers have an ongoing collaboration through a Hutchinson Center-based National Institutes of Health FSHD Program Project Grant, of which Tapscott is principal investigator. This paper is the second to emerge from this collaboration.
"The progress was made possible by an unusual degree of collaboration and data-sharing among the individual groups," Tapscott said.

###

Grants from the Friends of FSH Research, the Shaw Family Foundation and the Muscular Dystrophy Foundation also supported the work of Tapscott and colleagues at the Hutchinson Center.

FSHD Research - Field's Center

Sensing a Breakthrough - Rochester Medicine - Summer 2010 - University of Rochester Medical Center

Sensing a Breakthrough

Unique International Collaboration Advances Understanding and Treatment of a Muscular Dystrophy

By Michael Wentzel

Rabi Tawil, M.D.

When researchers pinpointed the genetic mutation that leads to the disease known as facioscapulohumeral dystrophy (FSHD) in 1992, hopes rose that the discovery not only would result in better treatments but also eventually a cure for the disease.
But FSHD, which was first described by French physicians in 1884, is an atypical genetic disease. While the discovery of the genetic defect on chromosome 4 opened new areas of research, it also added to the disease mysteries. This genetic defect involves the loss of a critical number of repetitive pieces of DNA, a sequence called D4Z4. At least 11 copies of the sequence are required for normal health. Those who have fewer than 11 get the disease.

Aerobic Exercise & Cognitive Therapy - FSHD

Effect of aerobic exercise training and cognitive behavioural therapy on reduction of chronic fatigue in patients with facioscapulohumeral dystrophy: protocol of the FACTS-2-FSHD trial Abstract Background In facioscapulohumeral dystrophy (FSHD) muscle function is impaired and declines over time. Currently there is no effective treatment available to slow down this decline. We have previously reported that loss of muscle strength contributes to chronic fatigue through a decreased level of physical activity, while fatigue and physical inactivity both determine loss of societal participation. To decrease chronic fatigue, two distinctly different therapeutic approaches can be proposed: aerobic exercise training (AET) to improve physical capacity and cognitive behavioural therapy (CBT) to stimulate an active life-style yet avoiding excessive physical strain. The primary aim of the FACTS-2-FSHD (acronym for Fitness And Cognitive behavioural TherapieS/for Fatigue and ACTivitieS in FSHD) trial is to study the effect of AET and CBT on the reduction of chronic fatigue as assessed with the Checklist Individual Strength subscale fatigue (CIS-fatigue) in patients with FSHD. Additionally, possible working mechanisms and the effects on various secondary outcome measures at all levels of the International Classification of Functioning, Disability and Health (ICF) are evaluated.

Myoblasts from affected and non-affected FSHD muscles

 Read complete manuscript @ https://mail.google.com/mail/?ui=2&view=bsp&ver=ohhl4rw8mbn4

Research study Manuscript for J Cell Mol Med
Marietta Barro 1 , Gilles Carnac 1 , Sébastien Flavier 1 , Jacques Mercier 1 2 , Yegor Vassetzky 3 , Dalila Laoudj-Chenivesse 1 *

Several papers support a role for oxidative stress as a pathological cause in FSHD [38 ,39 ]. Free radicals may be part of a cascade, and may provide a biochemical tool by which the pathological process can be inhibited. More studies on the action of radical oxygen species (ROS) and their sources may lead to a better understanding of the basis of FSHD.  Indeed, the demonstration that alterations in specific oxidant species or in their cognate antioxidant systems are a triggering event that leads to abnormalities in FSHD satellite cells would then have pathological value and represent molecular targets for therapeutic and diagnostic development.
 
In conclusion, this study shows that myoblasts derived from both clinically unaffected and affected muscles of patients with FSHD are more susceptible to oxidative stress than control myoblasts. Moreover, although myoblasts from patients affected with FSHD fully differentiated into multinucleated myotubes, they fused to form either thin and branched myotubes with aligned nuclei or large myotubes with random nuclei distribution. These two phenotypes might be the consequence of differences in oxidative stress sensitivity. Alternatively additional signaling pathways may contribute either independently or cooperatively with oxidative stress in FSHD. It has been shown that overexpression of FRG1 in transgenic mice induces skeletal muscle atrophy [9 ]. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, paired-like homeodomain transcription factor 1 (PITX1) was found specifically upregulated in patients with FSHD [14 ]. Since DUX4 protein can activate PITX 1 promoter, both DUX4 and PITX1 in FSHD muscles may play critical roles in the molecular mechanisms of the disease [14 ].
 

Therefore, these abnormalities could be responsible for the muscle weakness observed in patients with FSHD and provide an important marker for FSHD myoblasts.

Muscle Stem Cells - A Window into Cell Behavior

Muscle Stem Cells as Seen on Time Lapse Photography

By Rob Granter | Saturday,August 7, 2010

When muscle tissue experiences trauma or disease, such as muscular dystrophy, stem cells in the muscle known as “satellite cells” respond to repair and regenerate the muscle.


(click link to read whole article & view the time lapse movie of these cells)

CoQ10

Everything You Needed To Know About CoQ10

Some Information about CoQ10...
CoQ10 is a vitamin-like compound that is produced naturally in the human body and is also found in most living organisms. It is also called ubiquinone, a combination of quinone, a type of coenzyme, and ubiquitous, meaning it exists everywhere in the human body. CoQ10 plays an important role in your body’s energy production and is an essential component of the mitochondria, where it helps to metabolize fats and carbohydrates and maintain cell membrane flexibility. CoQ10 is also involved in the production of several key enzymes that are used to create ATP, which is burned by your body for energy, and in the energy transfer between mitochondria and cells. Without CoQ10, you would not be able to function!

More information is in this article, unfortunately no references are sited nor is there a name of the writer.
May present some data that should be verified.

Clinical profile and molecular diagnosis in patients of facioscapulohumeral dystrophy from Indian subcontinent Tamhankar PM, Phadke SR Neurol India

Clinical profile and molecular diagnosis in patients of facioscapulohumeral dystrophy from Indian subcontinent
Tamhankar PM, Phadke SR Neurol India

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscular dystrophy. We retrospectively studied three families (two Indian, one Nepalese) with 12 affected members (male:female-7:5). Mean age at onset of weakness was 17.63 + 5.48 years. Patients were classified according to muscle groups affected (F-face, S-scapula, H-humeral, PG-pelvic girdle, P-peroneal, A-loss of independent ambulation): FSH-A (2), four FSH (4), SH (3), FSH-PG (2) and one: F (1). Progression of weakness was classified as F>S>P>PG in eight cases, S> F>P in one, static in three. Eleven patients had electromyographic findings suggestive of myopathy and one had features of neurogenic involvement. Molecular diagnosis was done by southern blotting using probe p13E-11 after digestion of genomic DNA with EcoRI and/or EcoRI/BlnI for twelve patients and three unaffected relatives. No EcoRI fragment smaller than 35 Kb was seen in unaffected subjects. Size of EcoRI fragment varied between 17 kb to 27 kb in affected subjects and was constant for affected members of the same family. Molecular diagnosis by southern blotting has helped to provide genetic counseling for the families.

Myotonic Dystrophy & FSHD Registry - University of Rochester Medical Center

Newsletters - Myotonic Dystrophy & FSHD Registry - University of Rochester Medical Center

Learn more about the Registry at the University of Rochester.

Read their past newsletters & see how you might get involved in a study and help advance FSH research.

Scientists develop new way to grow adult stem cells in culture

Scientists develop new way to grow adult stem cells in culture



Scientists develop new way to grow adult stem cells in culture
July 15, 2010

Researchers at the Stanford University School of Medicine have developed a technique they believe will help scientists overcome a major hurdle to the use of adult stem cells for treating muscular dystrophy and other muscle-wasting disorders that accompany aging or disease: They've found that growing muscle stem cells on a specially developed synthetic matrix that mimics the elasticity of real muscle allows them to maintain their self-renewing properties.

Research connection - FSHD Global

Research connection


Monash University
Research connection
July 2010

For Dr Lucy Burns, (MBBS 1993) supporting Monash research into Facioscapulohumeral muscular dystrophy (FSHD) is a cause close to her heart.

The President of the Victoria Branch of the FSHD Global Research Foundation and Monash medicine alumna is living with FSHD - the most common form of adult muscular dystrophy - and as an inherited disorder, there is a 50 per cent chance her children will grow up to develop the disease.

The foundation has donated $160,000 to Professor Christina Mitchell's team to analyse the levels and distribution of novel proteins that regulate muscle mass in human FSHD skeletal muscle samples, and to study muscle wasting in a mouse model of the disease.

Clinical trials

Clinical trials | Muscular Dystrophy Campaign

FSHD Clinical Trials Currently seeking participants.

FSHD standards of care and clinical trial readiness

FSHD is the third most common muscle disorder and although no definite cure exists, careful management of the symptoms can lead to significant improvements in quality of life. This workshop brought together patient representatives, clinicians and scientists to define standards of care and discuss what is needed to lay the foundation for future treatments. Recommendations were based on evidence, when available, or on the consensus of expert opinion.
Four main topics were discussed:

* Diagnosis
* Clinical management
* Clinical trial readiness
Future Plans

Read more at http://www.muscular-dystrophy.org/research/news/2481

Medical Marijuana: - FSH Pain Management

Cañon City Daily Record - Medical Marijuana: Pro vs. Con

There are 21,625 registered medical marijuana patients in the state as of Oct. 31, 2009, according to the Colorado Department of Public Health and Environment, which is tasked by statute with issuing medical marijuana licenses.

Katy Klingbeil, 36, of Buena Vista, is one of those patients.

Klingbeil suffers from Facioscapulohumeral Muscular Dystrophy, FHS. The disease has caused her to lose muscle in her upper arms, shoulders, jaw and back.

Effect of aerobic exercise training

Effect of aerobic exercise training and cognitive ... [BMC Neurol. 2010] - PubMed result

Abstract

ABSTRACT: BACKGROUND: In facioscapulohumeral dystrophy (FSHD) muscle function is impaired and declines over time. Currently there is no effective treatment available to slow down this decline. We have previously reported that loss of muscle strength contributes to chronic fatigue through a decreased level of physical activity, while fatigue and physical inactivity both determine loss of societal participation. To decrease chronic fatigue, two distinctly different therapeutic approaches can be proposed: aerobic exercise training (AET) to improve physical capacity and cognitive behavioural therapy (CBT) to stimulate an active life-style yet avoiding excessive physical strain.

FSH presenting with hypertrophic cardiomyopathy: A case study

Facioscapulohumeral muscular dystrophy presenting with hypertrophic cardiomyopathy: A case study: "Abstract

Only three facioscapulohumeral muscular dystrophy (FSHD) patients have been reported to have cardiomyopathy. An asymptomatic 38-year-old man was incidentally found to have electrocardiographic abnormalities. His echocardiogram demonstrated mild dilatation of the left ventricle and poor contractility. Cardiac histopathology indicated hypertrophic cardiomyopathy. Later he developed muscle weakness in the right arm. Scapular winging and asymmetrical facial weakness were evident. Muscle biopsy at the age of 44 years showed myopathic changes consistent with FSHD. His daughter had symptoms of infantile FSHD, which was genetically confirmed. This is the first report of an FSHD patient with biopsy-proven cardiomyopathy."

Gene Therapy Shows Promise

Gene Therapy Shows Promise for Muscular Dystrophy | Science News

Scientists have succeeded in using gene therapy to restore some muscle function in patients with a certain type of muscular dystrophy.

“This study provides additional information regarding the feasibility of gene therapy for the treatment of muscular dystrophy,” said Dr. Valerie Cwik, executive vice president and research and medical director of the Muscular Dystrophy Association, which helped fund the research. “Specifically, it provides proof of principle, in people, for sustained gene expression [for at least six months] following treatment.”

This is the first time such a feat has been performed in humans, state the authors, who are presenting their findings at the annual meeting of the American Society of Gene & Cell Therapy in Washington, D.C.

(for more information, read the complete article)

genetic and epigenetic face of Facioscapulohumeral muscular dystrophy

The genetic and epigenetic face of Facioscapulohumeral muscular dystrophy
Silvère van der Maarel, PhD, Prof.

Autosomal dominant Facioscapulohumeral Muscular Dystrophy (FSHD) is the second most common myopathy in adults. FSHD is mainly characterized by progressive and often asymmetric weakness and wasting of the facial, shoulder and upper arm muscles. During disease progression, also other muscles may become affected. Frequently reported non-muscular symptoms include sensorineural deafness and retinovasculopathy, although these symptoms often go unnoticed. Genetically, FSHD is associated with a contraction of the D4Z4 macrosatellite repeat in the chromosome 4q subtelomere in the large majority of patients. In healthy individuals this polymorphic repeat varies between 11-100 D4Z4 units, each unit being 3,3kb in size. Patients with FSHD typically carry one allele with a D4Z4 repeat of 1-10 units.

Click here to read more

Life Without a Smile

MDA / Quest 4-3 / Life Without a Smile


COPING WITH FACIAL WEAKNESS IN FSHD

by Margaret Wahl

Songs tell us we're never fully dressed without a smile and exhort us to pack up our troubles in our old kit bags and -- smile, smile, smile. Smiling mouths tell us to buy everything from toothpaste and shampoo to diamonds and automobiles, and stylized "smiley faces" peer at us from posters and stickers.

There's more space in the brain devoted to muscle control of the face than to any other part of the body except the hands. And, a part of the brain known as the amygdala has as one of its specific functions the interpretation of other people's facial expressions.

Smiling is considered a milestone in a baby's life, one anxiously awaited by parents. ("Is it a smile, or is it just gas?" they wonder. "Is the baby connected to us yet?")

But, what about people, like many with facioscapulohumeral muscular dystrophy (FSHD), who can't smile? For many with this condition, weakness in the facial muscles makes any facial expression difficult, and smiling is particularly hard.

Paul Topkin of Lakeland, Fla., has his picture taken fairly often, mostly because of his recent fame as a builder of replicas of historic ships that sell for thousands of dollars to individuals and corporations.

Some people might see a photo of the 56-year-old Topkin and think he's a rather grim-looking artist, perhaps in need of treatment for depression. But Topkin has FSHD and, despite a lively sense of humor, he can't smile.

To Read More

DUX4c Is Up-Regulated in FSHD

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to contractions of the D4Z4 repeat array in 4q35. We have previously identified a double homeobox gene (DUX4) within each D4Z4 unit that encodes a transcription factor expressed in FSHD but not control myoblasts. DUX4 and its target genes contribute to the global dysregulation of gene expression observed in FSHD. We have now characterized the homologous DUX4c gene mapped 42 kb centromeric of the D4Z4 repeat array. It encodes a 47-kDa protein with a double homeodomain identical to DUX4 but divergent in the carboxyl-terminal region. DUX4c was detected in primary myoblast extracts by Western blot with a specific antiserum, and was induced upon differentiation. The protein was increased about 2-fold in FSHD versus control myotubes but reached 2-10-fold induction in FSHD muscle biopsies. We have shown by Western blot and by a DNA-binding assay that DUX4c over-expression induced the MYF5 myogenic regulator and its DNA-binding activity. DUX4c might stabilize the MYF5 protein as we detected their interaction by co-immunoprecipitation. In keeping with the known role of Myf5 in myoblast accumulation during mouse muscle regeneration DUX4c over-expression activated proliferation of human primary myoblasts and inhibited their differentiation. Altogether, these results suggested that DUX4c could be involved in muscle regeneration and that changes in its expression could contribute to the FSHD pathology.

Read Complete research report

Toolbar for FSH Research

Another way you can help MAKE A DIFFERENCE!

It's the new Pacific Northwest Friends of FSH Research toolbar - once added to IE or Firefox, each time you shop at more than 1,300 stores (from Amazon to Zazzle!) a percentage of your purchase will automatically be donated to Pacific Northwest Friends of FSH Research - at no cost to you (and you may even save money as the toolbar provides coupons and deals as well!).
The toolbar also has a search box and each time you search the Internet, about a penny is donated to Pacific Northwest Friends of FSH Research.

http://www.goodsearch.com/toolbar/pacific-northwest-friends-of-fsh-research