Bethesda, MD, August 8, 2002 - A newly identified genetic problem underlies a common neuromuscular disorder called facioscapulohumeral muscular dystrophy (FSHD), scientists say. In a new study, they
show that deletion of repetitive DNA sequences in people with this disorder allows nearby genes to go into overdrive. The finding solves a decade-old riddle about the cause of this disorder and may ultimately lead to the first effective treatments.
The study found that abnormally short strings of repeated
DNA sequences on chromosome 4 interfere with the function
of a protein complex that controls nearby genes. This
leads to over-activity of several genes that may play a
role in the disorder. This type of genetic problem has
never before been identified in a human disease. The study
was funded in part by the National Institute of
Neurological Disorders and Stroke (NINDS) and appears in
the August 9, 2002, issue of Cell.*
Scientists first linked the short strings of DNA in this
region to FSHD in 1992. People with FSHD typically have
fewer than 11 copies of this nucleic acid sequence, called
D4Z4, due to a deletion of part of the chromosome. In
contrast, people without the disorder usually carry between
11 and 150 copies of the sequence. People with a very
small number of copies (three or fewer) have severe disease
symptoms that begin in childhood, while those with several
more copies typically have milder symptoms that begin in
the teens or early adulthood. However, until now,
researchers have been unable to determine exactly how the
number of DNA sequences influences the disease.
FSHD is the third most common inherited neuromuscular
disorder, affecting one in every 20,000 people (only
Duchenne muscular dystrophy and myotonic dystrophy are more
common). People with FSHD have progressive muscle
degeneration that primarily affects the face, shoulder
blades, and upper arms, although other muscles also
deteriorate. Despite intensive efforts, researchers have
been unable to identify any genes that are altered in this
In the new study, Rossella Tupler, M.D., Ph.D., of the
University of Massachusetts Medical School in Worcester and
the Universita' degli Studi di Pavia in Pavia, Italy, and
colleagues studied human muscle tissue from healthy
individuals and from people with FSHD as well as several
other types of muscular dystrophy. They analyzed the
expression of three genes located near the D4Z4 region and
found that activity of all three genes was elevated in the
muscle from FSHD patients compared to that of other people.
The researchers also analyzed the interaction between the
D4Z4 sequence and proteins present in the nucleus of the
cell. They found that one part of the sequence binds to a
protein complex that normally suppresses gene activity.
Having fewer than 11 copies of D4Z4 reduced the number of
functional protein complexes, which in turn reduced control
of genes from nearby parts of the chromosome.
"This breakthrough is important scientifically, as it
teaches us about novel ways genes can influence disease,
which will someday help not only those people who suffer
from FSHD, but hopefully, others as well," says Katrina
Gwinn-Hardy, M.D., a program director at NINDS.
The researchers do not know which of the overactive
chromosome 4 genes is responsible for the symptoms of FSHD.
One of the genes they considered, called ANT1, triggers
cell death when it is too active. Therefore it may be
responsible for the progressive loss of muscle cells in
this disorder. However, FSHD is a complex disease, and
other genes or environmental factors also may play a role.
"These findings have specific implications for the disease,
and general implications for genetic research," says Dr.
Tupler. Knowing how the D4Z4 deletions affect nearby genes
points to new strategies for treating the disorder. For
example, researchers might be able to find a way to mimic
the effect of the protein complex that goes awry in this
disorder, thereby reducing the activity of all the affected
genes. If a specific gene that causes the disorder can be
identified, researchers also might be able to slow or halt
that gene's activity with drugs or other treatments.
While most people with FSHD have D4Z4 deletions, about 5 to
10 percent do not. These people may have mutations that
affect the protein complex, Dr. Tupler says. Researchers
have also identified people without FSHD who are missing
the entire D4Z4 region and several nearby genes. This
suggests that an abnormal D4Z4 region somehow creates havoc
in muscle cells and/or that the nearby genes are necessary
for development of the disease.
The findings also suggest that repetitive DNA sequences
play a previously unsuspected role in human disease by
influencing gene activity, Dr. Tupler says. About 40
percent of the human genome is comprised of these
repetitive sequences, and they might play a role in several
other human disorders. For example, certain variations in
repetitive DNA sequences near the insulin gene in Type 1
diabetes have been linked to insulin levels and birth size.
Other DNA repeats have been associated with bladder cancer.
Studies of sequences like these could lead to a much better
understanding of how gene activity is regulated, Dr. Tupler
Scientists can now focus on identifying which genes on
chromosome 4 contribute to FSHD and how to regulate the
gene activity, says Dr. Tupler. "Hopefully, other
researchers will help with that," she adds.
The NINDS is a component of the National Institutes of
Health in Bethesda, Maryland, and is the nation's primary
supporter of biomedical research on the brain and nervous
* Gabellini D, Green MR, Tupler R. "Inappropriate gene
activation in FSHD: A repressor complex binds a chromosomal
repeat deleted in dystrophic muscle." Cell, Vol. 110,
No. 3, August 9, 2002, pp. 339-348.