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From: NIH news releases and news items [mailto:[log in to unmask]] On
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Sent: Thursday, August 19, 2010 2:13 PM
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Subject: DISCOVERY OPENS DOOR TO THERAPEUTIC DEVELOPMENT FOR FSH MUSCULAR
DYSTROPHY

U.S. Department of Health and Human Services 
NATIONAL INSTITUTES OF HEALTH NIH News 
National Institute of Neurological Disorders and Stroke (NINDS)
<http://www.ninds.nih.gov/>
Embargoed for Release: Thursday, August 19, 2010, 2 p.m. EDT  

CONTACT: Daniel Stimson, NINDS, 301-496-5751,
<e-mail:[log in to unmask]>

DISCOVERY OPENS DOOR TO THERAPEUTIC DEVELOPMENT FOR FSH MUSCULAR DYSTROPHY

Scientists are closer to understanding what triggers muscle damage in one of
the most common forms of muscular dystrophy, called facioscapulohumeral
muscular dystrophy (FSHD).

FSHD affects about 1 in 20,000 people, and is named for progressive weakness
and wasting of muscles in the face, shoulders and upper arms.  Although not
life-threatening, the disease is disabling.  The facial weakness in FSHD,
for example, often leads to problems with chewing and speaking.

The new research was funded in part by the National Institutes of Health and
appears in the journal Science.  Until now, there were few clues to the
mechanism of FSHD and essentially no leads for potential therapies, beyond
symptomatic treatments, said John Porter, Ph.D., a program director at NIH's
National Institute of Neurological Disorders and Stroke (NINDS).  

"This study presents a model of the disease that ties together many complex
findings, and will allow researchers to test new theories and potential new
treatments," Dr. Porter said. 

In the early 1990s, researchers found that FSHD is associated with a
shortened DNA sequence located on chromosome 4.  Experts predicted that
discovery of one or more FSHD genes was imminent, but while a handful of
candidate genes gradually emerged, none of them were found to have a key
role in the disease.

The mysteries surrounding FSHD deepened in 2002 when researchers, led by
Silvere van der Maarel, Ph.D., at Leiden University in the Netherlands,
found that the shortened DNA sequence on chromosome 4 is not enough to cause
FSHD.  They discovered that the disease occurs only among people who have
the shortened DNA sequence plus other sequence variations on chromosome 4.
That work was funded in part by NIH, the FSH Society and the Muscular
Dystrophy Association.  

The new study proposes a model that explains how the previous findings fit
together.  The study was led by Dr. van der Maarel in collaboration with
Stephen Tapscott, M.D., Ph.D., at the Fred Hutchinson Cancer Research Center
in Seattle, and Rabi Tawil, M.D., at the University of Rochester Medical
Center in New York.  

At one end of chromosome 4 is a chunk of repetitive DNA, called a tandem
repeat array.  Normally this region contains 10-100 repeating units of DNA,
but in most people with FSHD, the array is smaller, with fewer than 10
repeats.  Within each repeating unit is a gene called DUX4.

The researchers found that in people with FSHD, the DUX4 gene generates a
piece of RNA that is toxic to muscle cells.  RNA is a sister molecule to DNA
with many critical functions.  The researchers also discovered that
variations on chromosome 4 are important because they affect the durability
of DUX4 RNA.  People with FSHD have chromosome variations that add a
trailing segment to the RNA called a poly(A) tail.  With the poly(A) tail
attached, the RNA is more stable and more likely to cause damage.

The researchers came to these conclusions by creating artificial DNA
constructs containing the short repeat array, in combination with different
variations on chromosome 4.  They inserted these constructs into muscle
cells, and analyzed how the chromosome 4 variations affected the level of
DUX4 RNA.  They also studied FSHD families with unique chromosome
rearrangements and showed that all families with FSHD shared chromosome 4
sequences encoding the poly(A) tail.

In another set of experiments, they found they could detect DUX4 RNA in
muscle cells from individuals with FSHD but not in cells from unaffected
individuals.  Meanwhile, previous studies have shown that DUX4 can trigger
muscle cell death.

"This study provides evidence that DUX4 RNA is likely a key part of the
disease process in FSH muscular dystrophy, and justifies further
investigation of its role and how to silence its effects," Dr. Tapscott
said.

In addition to NINDS, the study received support from NIH's National
Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the
FSH Society, the Fields Center for FSHD and Neuromuscular Research, the
Muscular Dystrophy Association, the Shaw Family Foundation, the Pacific
Northwest Friends of FSH Research, the Netherlands Organization for
Scientific Research, the Netherlands Genomics Initiative, and other
organizations abroad.

For more information about muscular dystrophy, please visit
<http://www.ninds.nih.gov/disorders/md/detail_md.htm>.

NINDS (www.ninds.nih.gov) is the nation's leading funder of research on the
brain and nervous system.  The NINDS mission is to reduce the burden of
neurological disease -- a burden borne by every age group, by every segment
of society, by people all over the world. 

The mission of NIAMS (www.niams.nih.gov) is to support research into the
causes, treatment, and prevention of arthritis and musculoskeletal and skin
diseases; the training of basic and clinical scientists to carry out this
research; and the dissemination of information on research progress in these
diseases.

The National Institutes of Health (NIH) -- The Nation's Medical Research
Agency -- includes 27 Institutes and Centers and is a component of the U.S.
Department of Health and Human Services. It is the primary federal agency
for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.
-----------------------
REFERENCE:  Lemmers et al. "A Unifying Genetic Model for Facioscapulohumeral
Muscular Dystrophy," Science, published online August 19, 2010.
  
##

This NIH News Release is available online at:
<http://www.nih.gov/news/health/aug2010/ninds-19.htm>.

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