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FSH Society Hails Major Breakthrough in FSH Muscular Dystrophy

Watertown, MA--Daniel Perez, co-founder, President and CEO of the FSH Society and a 48-year-old patient with facioscapulohumeral muscular dystrophy (FSHD), the most common form of muscular dystrophy, hailed new findings,1 published today in Science that revealed for the first time the biological mechanism causing FSHD. “This is a long-sought explanation of the exact biological workings of a disease that affects an estimated one in 14,000 or 22,100 Americans and 490,000 worldwide,” he said, adding that this discovery “creates an enormous opportunity for research to develop ways to prevent or treat FSHD.” The study, titled “A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy,” was conducted by researchers from Leiden University in The Netherlands, the Fred Hutchinson Cancer Research Center in Seattle, Washington, and the University of Rochester Medical Center in New York.

“We are calling on the National Institutes of Health to immediately find ways to confirm and exploit these important findings, which I believe will generate great hope where there has been none,” he said. “It is truly a potential watershed moment, and we are cautiously optimistic that we are entering into a new phase of research.”

FSHD is a life-long, progressive, and severe loss of all skeletal muscles (face, shoulders, girdle and upper arms and progressing to the legs and feet). A crippling and life shortening disease, it is genetically and spontaneously (by mutation) transmitted to children, and it affects entire family constellations. Until now, there has been little definitive evidence of the exact genetic package that triggers the disease.

"These most recent findings begin to define a pathway to treatment for FSHD," said Professor David Housman of MIT, Chairman of the FSH Society's Scientific Advisory Board. “Understanding how a quiescent ancestral gene that is seemingly tucked away in a forgotten corner of the human genome can reemerge to cause muscle weakness and wasting in tens of thousands of people around the world is a fascinating scientific story,” he said. “But more importantly, the knowledge that has emerged from tracking this complex story of DNA slipping and sliding into a deadly configuration opens the door to new ways to prevent damage from being done and an eventual return to health for victims of this very common form of muscular dystrophy."

Said Nancy Van Zant, Executive Director, FSH Society: “Patients ask us every day if there is any hopeful research to share. We are always optimistic for them, but progress has seemed slow. Now, the reality that a specific genetic package of material leads to the toxicity causing the disease means that researchers can focus efforts to test medications on this defined target. Speaking as one of the leaders of this organization, I look forward to participating in the coordination of financial resources and patient efforts to help investigators carry this finding forward into treatments.”

1. Lemmers et al. “A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy,” Science, published online August 19, 2010.


About the FSH Society's Role in the Science Paper Breakthrough

The FSH Society is a 501(c) (3) non-profit patient-led research, education and advocacy organization, founded in 1991. The Society frequently testifies before Congress on the research needs in FSHD. It has funded $2.3 million in $30,000-45,000 a year fellowships to more than five dozen researchers in 11 years, leading to well over a hundred publications in top tier journals.

Researcher(s) that published this Science paper have been recipients of FSH Society support and also serve as members of the FSH Society Scientific Advisory Board. Both the first and last authors, Drs. Richard Lemmers and Silvere van der Maarel began their careers in FSHD research as recipients of the prestigious FSH Society Marjorie Bronfman fellowship awards. The FSH Society has provided the Leiden team and many of their partners with funds to support early phases of their work.

The FSH Society is a small non-profit with a very dedicated and gifted group of scientific advisors, headed by Prof. David E. Housman, Massachusetts Institute of Technology, and along with its board of directors comprised mainly of patients and with the generous support of thousands of affected FSHD families and family foundations, the Society has helped to solve the mechanism causing FSHD. It has carefully raised funds and targeted many areas of research needed to be examined in FSHD and layered in the foundation for discovery.”

The FSH Society has funded many other projects with researchers around the globe who have published on FSHD in recent years; Drs. Jane Hewitt, Peter Jones, Ryan Wuebbles, Michael Kyba, Darko Bosnakovski, and Sara Winokur. All of these findings and papers along with the current breakthrough paper provide the context in which how to approach treating FSHD becomes apparent. This truly demonstrates the effectiveness of patient driven and disease focused organizations.

The FSH Society helps the DHHS NIH FSHD patient registry and existing DHHS NIH Sen. Paul D. Wellstone FSHD Cooperative Research Center at the Boston Biomedical Research Institute. The Society is composed of a board of directors of affected persons or family members and has over 4,000 members.

1. Lemmers et al. “A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy,” Science, published online August 19, 2010.


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A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy

Richard J.L.F. Lemmers1, Patrick J. van der Vliet1, Rinse Klooster1, Sabrina Sacconi2, Pilar Camaño3,4, Johannes G. Dauwerse1, Lauren Snider5, Kirsten R. Straasheijm1, Gert Jan van Ommen1, George W. Padberg6, Daniel G. Miller7, Stephen J. Tapscott5, Rabi Tawil8, Rune R. Frants1, Silvère M. van der Maarel1,*

1. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
2. Centre de reference pour les maladies Neuromusculaires and CNRS UMR6543, Nice University, Nice, France
3. Department of Neurosciences, BioDonostia Health Research Institute, Hospital Donostia, San Sebastián, Spain
4. CIBERNED, Instituto de Salud Carlos III, Spain
5. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
6. Department of Neurology, Radboud University Medical Center Nijmegen, Nijmegen, The Netherlands
7. Department of Pediatrics, University of Washington, Seattle, WA, USA
8. Department of Neurology, University of Rochester Medical Center, NY, USA

*To whom correspondence should be addressed. E-mail:

Abstract: Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35 but this contraction is pathogenic only in certain “permissive” chromosomal backgrounds. Here we show that FSHD patients carry specific single nucleotide polymorphisms (SNPs) in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings Lemmers et al 2 suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.


A Note on the Origins of this Research

Richard Lemmers' work on the allelic variants was supported by the FSH Society Marjorie Bronfman Fellowship Award, 2005-2009. Both the first and last authors, Drs. Silvere van der Maarel and Richard Lemmers have been the recipients of the prestigious FSH Society Marjorie Bronfman fellowship awards.

FSH Society Marjorie Bronfman Post-Doctoral Research Fellowship
Grant: FSHS-MGBF-010
Researcher: Richard Lemmers, MSc., Ph.D.*
Institution: Leiden University Medical Center
Project Title: “Refinement of the FSHD critical region on 4qA chromosomes.”

$35,000 6/15/2005 – 6/14/2006 Year 1
$35,000 6/15/2006 – 6/14/2007 Year 2
$35,000 2/15/2008 – 2/14/2009 Year 3

Goal: [Provided by FSH Society Grant Applicant] FSHD is the third most common myopathy, with an autosomal dominant mode of inheritance. FSHD is caused by contraction of the polymorphic D4Z4 repeat in the subtelomere of chromosome 4q and the exact pathogenic mechanism is still unclear. An identical and equally polymorphic D4Z4 repeat is localized on chromosome 10, but this has never been associated with FSHD. Our approach of detailed characterization of FSHD alleles and translating these observations to disease mechanisms has provided robust mechanistic insight in FSHD pathogenesis over the past years, including the mechanism of mitotic D4Z4 instability (Lemmers et al. 2004a) and the recognition of a bi-allelic 4qter variation (designated 4qA and 4qB) of which only the 4qA allele is associated with FSHD (Lemmers et al. 2002). Moreover, our laboratory provided direct evidence for a chromatin modification associated with the contraction of D4Z4 repeats by demonstrating hypomethylation of D4Z4 in FSHD alleles (van Overveld et al. 2003).

Through our expertise in pulsed-field gel electrophoresis (PFGE)-based FSHD allele characterization, we have become the international reference center for FSHD diagnosis with on average 50 referrals of atypical FSHD patients each year and culminating in a database of>l000 patient and control genotypes for D4Z4 alleles on chromosomes 4 and 10. Our PFGE-based D4Z4 examination has led to further refinement of minimal requirement to develop FSHD in several ways including exclusion of a region of 55 kb proximal to D4Z4 by identification of proximally extended deletions in typical FSHD patients (Lemmers et al. 2003). Moreover, and novel to this field, our analysis provides evidence that within an FSHD repeat, not all units are equal, suggesting that intrinsic differences between individual D4Z4 units within one array may be important for PSEID pathogenesis (Lemmers et al. 2004a).

In the current application I propose to further refine the minimal region necessary and sufficient to cause FSHD in two ways. First, I will precisely characterize three novel patients with an unusual FSHD allele. Two of these alleles carry, analogous to proximally extended deletions, deletions of sequences distal to D4Z4. The third pathogenic allele is highly unusual, because preliminary data suggest that it is located on chromosome 10. The analysis of these alleles will be combined by the full characterization of FSHD and control alleles that display repeal exchanges between chromosome 4 and 10. Moreover, I will focus on intrinsic sequence differences between 4qA-, 4qB and 10q-derived D4Z4 units, most notably that of the most proximal unit, as we provided evidence for a linkage disequilibrium (LD) between this D4Z4 unit and the distal polymorphism 4qA or 4qB (Lemmers et al. 2004a).

I expect that this proposal will generate new and essential information on the minimal region that is required to develop FSHD. Considering the complexity of the disease mechanism, further refinement of these elements is essential for a better understanding of the primary pathogenic pathway and will assist future research strategies based on candidate gene approaches and development of appropriate cellular and animal model systems.

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