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In the Spotlight:
Fields Center Scientists Pinpoint the Genetic Cause of FSHD type 2
Fields Center Scientists, in a new study published in the journal Nature Genetics on November 11th, made an important discovery leading to the identification of the gene that causes FSHD type 2 (FSHD2). In 2010 Fields Scientists published an article identifying the cause of FSHD type 1 which accounts for about 95% of cases of FSHD. Intensive research over the last several years has now resulted in identifcation of the genetic cause of FSHD2 (click here for the UR press release for details) .
FSHD1 is caused by a loss of a large number of repetitive pieces of DNA on chromosome 4 that loosens the DNA structure and allows a gene called DUX4 to be turned on. DUX4 is usually turned off in mature tissue like muscle and is toxic to muscle fibers when it is abnormally turned on. Patients with FSHD2 have a normal number of repeats on chromsome 4 and yet have a loosened DNA structure on chromosome 4, just like individuals with FSHD1, that allows the abnormal turning on of the DUX4 gene. Fields Center scientists reasoned that another gene is responsible for this change in the DNA structure. By examining a number of familiies with FSHD2, the have uncovered defects in another gene called SMCHD1. The defective SMCHD1, has now been shown to cause the unraveling of the DNA structure on chromosome 4.
This study is the result of a close international collaboration of Fields Center Scientists at the University of Rochester Medical Center, the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle as well as Leiden University Medical Center in the Netherlands.
New Publication from Fields Center Scientist About DUX4 Methylation
A new publication by Fields Center scientist examines the role of methylation in FSHD. The degree of methylation on the tip of chromosome 4 determines how tightly bound the DNA. The Center scientists have previously shown that low methylation levels in DNA derived from blood results in more open DNA structure and allows the expression of the DUX4 gene which is normally silenced. They have now confirmed these changes in a large number of samples of DNA derived from muscle cells as well as from DNA from fibroblast cells derived from skin. In addition to the Fields Center, funding for this study was provided by the Geraldi Norton Foundation and the Eklund Family, NIH as well as scientific grants from the Netherlands.
Fields Center Scientist Receives Prestigious World Muscle Society Award
A Fields Center scientist, Dr. Richard Lemmers working in Leiden, The Netherlands was awarded the World Muscle Society's President Prize for Young Myologist of the Year. This presitigious prize was awarded to Dr. Lemmers during the
16th International World Muscle Society Congress held on October 18-22nd, 2011 in Almancil, Portugal. This prize was awarded for Dr. Lemmers significant contributions to FSHD research. Dr. Lemmers research, working in Dr. Silvere van der Maarel laboratory as part of the Fields Center collaborative research effort, was instrumental in the recent determination of the importance of the DUX4 gene in FSHD. Dr. Lemmers was the lead author in the pivotal Science journal article that provided the first solid proof that the DUX4 gene played a major role in causing FSHD.
Fields Center Scientist Publish Review Article
Fields Center scientists publish a review article describing the latest findings on the molecular mechanism of FSHD in Trends in Molecular Medicine.
Highlights from the 3rd Annual Patient Day on Saturday, September 18, 2010
What an exciting time to gather to talk about FSHD research! In August 2010, Fields Center researchers published their breakthrough findings about the genetic mechanism responsible for FSHD – findings that took almost 20 years to discover! Our 3rd Patient Day was the first opportunity after our findings were released where patients and family members could hear, firsthand, how DUX4 causes FSHD. DUX4, a gene that makes a protein harmful to muscle cells, is more active than it should be in some people, resulting in the disease. After an exciting keynote address by Mr. Kees van der Graff, president of the Dutch FSHD Foundation, attendees were treated to a day full of presentations describing these research findings and the best practices for medical care. Along the way, some of our less camera shy guests gathered for a quick photo while others chatted over dessert.
At the end of the day, our guests reported the following:
- Attendees gave this conference an overall rating of “Excellent,”
- 100% of respondents indicated that they would return for a future conference, and
- 100% of those responding said they would recommend that other people attend a future Fields Center Patient Day as well.
We were honored to open and close the meeting with the personal stories of people with FSH dystrophy, stories that were touching and inspirational. These sessions received the highest approval ratings of all!
For people unable to attend this year, we are pleased to post links to this year’s presentations on our website for review. To access these materials, click here. The Fields Center Directors offer special words of thanks to our presenters for sharing their expertise! We hope that you will find these slides informative and that you will consider joining us next year to hear these talks in person. Until then, we encourage you to check our website regularly for updates and for information on next year’s meeting! Hope to see you there!
Rabi Tawil, MD Silvere van der Maarel, PhD
Fields Center scientists publish two additional research articles on FSHD
Two new articles by Fields Center scientists were published in October providing further support of the breakthrough discovery published in the Science article published in August of 2010.
The first article, published in the online journal PLoS Genetics, provides further proof of the unifying theory of FSHD published recently. The present article shows that protein from the DUX4 gene, normally expressed only in germline cells (sperms and eggs) continues to be expressed in individuals with FSHD whereas it is turned off in individuals who do not have the FSHD genetic defect. This new information provides further support to the idea that one treatment approach will be to try to suppress the expression of this gene.
The second publication, published in the journal Neurology with Dr. Rabi Tawil as senior author, provides additional description of patients with FSHD type 2 (FSHD2). Such patients, who represent less than 5% of individuals with FSHD do not have the loss of the D4Z4 repeat DNA on chromosome 4. They, however, have the same unwinding of the chromosome structure that is seen in patients with loss of the D4Z4 repeats. The present investigation shows that individuals with FSHD2 are clinically identical to the common form of FSHD (also known as FSHD1). The evidence also support that fact that although FSHD1 and FSHD2 may have genetic differences at the DNA level, they ultimately cause FSHD through a similar mechanism.
Fields Center scientists publish breakthrough research on FSHD
Fields Center scientists make an important discovery (click here to view UR press release) that significantly advances our understanding of the disease mechanism in FSHD. The scientists’ findings were published today in the prestigious journal Science (click here to view article). For a number of years, the genetic defect resulted in muscle weakness in FSHD remained unknown and several theories were proposed but none of which could be confirmed. The present research provides a unifying theory as to the mechanism underlying FSHD and identifies the probable gene (DUX4) whose malfunction results in FSHD. As a result of this discovery, scientists now have a target to go after for developing treatments for FSHD.
Fields Center researchers land $6 million NIH Grant
Building on the successful research work and infrastructure established over the past two years, the scientists and collaborators from the Fields Center for FSHD & Neuromuscular Research have secured a $6 million dollar, five year grant to continue their ground-breaking efforts. This grant comes in the form of an FSHD (FSH dystrophy) Program Project Grant from the National Institute of Neurological Disorders and Stroke NINDS. The award provides funding for multiple integrated and coordinated research projects on FSHD to be conducted at multiple institutions world-wide. Acknowledging and rewarding the pioneering efforts of the Fields Center investigators - Rabi Tawil (Rochester, NY), Silvere van der Maarel (Leiden, The Netherlands) and Stephen Tapscott (Fred Hutchinson Cancer Research Center) - the Program Project also supports research projects by Daniel Miller (University of Washington) and Galina Filippova (Fred Hutchinson Cancer Research Center). And, in keeping with the Fields Center’s core image, the “Center Without Walls,” this grant will further collaborations with a number of scientists in the United States, Belgium and France that are leading the way down solid pathways to progress.
This Program Project represents the largest coordinated research work on FSHD to date and is one of the largest NIH grants awarded to researchers in the Netherlands. This funding is gratefully accepted as it will help us continue to make solid advances and to accelerate the rate of progress in FSHD research.
The Fields Center’s “Best Practice Meeting for the DNA Diagnosis of Facioscapulohumeral Muscular Dystrophy (FSHD)” was held on June 9, 2010 at the Leiden University Medical Center, Leiden, The Netherlands. Forty-seven participants from sixteen countries participated in this workshop. The primary objective of the workshop was to develop guidelines for the DNA diagnosis of FSHD. The first half of the meeting included lectures on the clinical and genetic diagnosis of FSHD. During the second half of the meeting, recommendations were formulated based on an earlier distributed questionnaire, experience, and on the consensus of expert opinion. These guidelines will be drafted into a manuscript for further dissemination. The Fields Center Directors want to recognize the following organizations for providing financial support for this meeting: The Fields Center for FSHD & Neuromuscular Research, The Dutch FSH Foundation, Global FSHD, The FSH Society, Spieren voor Spieren ("Muscles for Muscles") and the Muscular Dystrophy Association. Thank you for underwriting this important effort!
Best Practice Meeting for the Molecular Diagnosis of FSHD - June 9, 2010
During the highly successful European Neuromuscular Center FSHD Workshop in Jan 2010, attendees concluded that there was a need for further discussion to better define the “gold standard” for diagnostic procedures for FSHD. With evidence of the increasing complexity of the genetics of FSHD, it is important to reach an international consensus on the molecular testing methods. To that end, Fields Center investigators (Richard Lemmers, PhD; Silvere van der Maarel, Ph.D.; and Rabi Tawil, MD) invited key colleagues from around the world to join them at the Leiden University Medical Center on June 9, 2010 to participate in the “Best Practice Meeting for the Molecular Diagnosis of FSHD”. The goal of the meeting is to generate consensus regarding the genetic testing protocol for FSHD. Topics for discussion will include: current status of testing in different laboratories worldwide, recent developments regarding the genetics of FSHD, the diagnosis of FSHD2, new technologies, and prenatal diagnosis. Confirmed speakers include Prof Dr Bert Bakker (Leiden, Netherlands), Dr. Yukiko Hayashi (Tokyo, Japan), Dr. Richard Lemmers (Leiden, Netherlands), Dr. Nicolas Levy (Marseille, France), Dr. Peter Lunt (Bristol, UK), Dr. Suzanne O’Shea (Bristol, UK), Dr. George Padberg (Nijmegen, The Netherlands), Dr. Rossella Tupler (Modena, Italy) and Dr. Meena Upadhyaya (Cardiff, UK).
Response to the meeting invitation has been excellent to date. Participants were asked to complete a questionnaire prior to the meeting to provide information that will be discussed when the group assembles. This step will help gather and disseminate best practice options from participants who are active and interested in genetic diagnosis of this complex disease. Upon completion of the meeting, the recommendations of the assembly will be published for use by the scientific and medical communities.
Recognizing the importance of this effort, the following organizations generously agreed to financially sponsor this meeting:
- The Fields Center for FSHD & Neuromuscular Research
- The Dutch FSH Foundation
- Global FSHD
- The FSH Society
- Spieren voor Spieren ("Muscles for Muscles")
- Muscular Dystrophy Association
- AFM (Association Francaise contre les Myopathies),
Please join us in thanking them for their contributions toward the success of this endeavor!
On January 15 – 17, 2010 in Naarden, The Netherland, the Fields Center helped organize and sponsor a European Neuromuscular Center FSHD Workshop. Twenty-four participants met to develop standards of care in diagnosis and management of patients with FSHD. A manuscript entitled “171st ENMC International Workshop: Standards of care and management of facioscapulohumeral muscular dystrophy” was developed from the discussions at this meeting. Please click on the link below to view the manuscript that was published in the Neuromuscular Disorders journal.
European Neuromuscular Center FSHD Workshop Jan 15-17, 2010 :
The Fields Center investigators along with colleagues from the Netherlands have organized an international conference on "Standards of Care and Management of FSHD". This worshop is sponsored by the European Neuromuscular Center (ENMC) and will be held in Naarden, The Netherlands, on January 15-17, 2010. This workshop will outline standards of care for FSHD as well as develop outcome measures to be used in future clinical trials.
First International Donation received from Mr. Daniel Frenzel
Mr. Daniel Frenzel, of Germany, contacted us by email to inquire about donating to Fields Center research programs. We were honored to receive a sizeable donation from Mr. Frenzel shortly thereafter. His gift will be support a joint project conducted in Rochester, Leiden and at the Institut de Myologie in Paris to create immortalized cells lines that originate from muscle biopsy samples taken from individuals with FSHD. These cell lines are ideal to study the underlying mechanisms that lead to FSHD and can be used to test for treatments that reverse the effects of the genetic defect on the muscle. Mr. Frenzel told us that he donated to the Fields Center and to FSH research “because then others may do they same.” Thank you, Mr. Frenzel, for your leadership and support! We hope that your example encourages others to participate in or to donate to FSH research. Your donation will make a real and immediate difference on the research conducted on two continents!
Flint Creek Band benefit concert
The Fields Center received a call from a patient and long-time supporter of FSH research at the University of Rochester, informing them that the Flint Creek Band was playing a benefit concert in Shortsville, NY, on September 19, 2009. A portion of the proceeds from the concert were donated to the Fields Center to apply toward FSH research projects. This donation is our first donation from people who have participated in our studies and who, hopefully, may benefit from this work. We are grateful to our patient and to Flint Creek for including the Fields Center in the array of worthy causes that need the support and participation of patients and community members.
Archived In the Spotlight:
For more information, please contact the Fields Center FieldsCenter@urmc.rochester.edu