Mutations in genes that modify DNA
packaging result in Facioscapulohumeral Muscular Dystrophy type 2.
Friends of
FSHD Research has helped fund another ground breaking project that has shed new
light on the mechanism of muscle damage in Facioscapulohumeral Muscular
Dystrophy, and suggests new targets for treatment.
In today’s issue of Nature Genetics, Dr. Daniel G. Miller and Dr. Silvere M. van der
Maarel of Leiden University in The Netherlands, along with an international
team, report their latest findings that expand the role of epigenetic
modifications in causing the disease.
Epigenetic
s refers to mechanisms that influence how the genome is regulated and how,
where and when genes act -- all without altering the underlying DNA sequence. The flexibility of DNA packaging – its
wrapping, which can be tightened and loosened, and its chemical tags – is one
of the epigenetic forces on the genome. This packaging is called the chromatin
structure and is one way specialized cells such as those in our muscles allow
groups of genes to be shut off, or be available for expression.
People
with FSHD, usually have a deletion of genetic material that reduces the number
of copies of a repeated DNA sequence arrayed on chromosome 4. In a previous
study let by Dr. Stephen Tapscott, Friends-sponsored Scientists showed that the
genetic deletions in FSHD somehow caused an epigenetic change – an alteration
in one of the mechanisms that control a gene’s activity. The relaxation of the tightly wound chromatin
structure allowed the otherwise sealed code in the gene to be read and the
toxic DUX4 to be produced in skeletal muscle. Thus the muscle-toxic DUX4 genes
within each repeat become inappropriately activated in the wrong tissue at the
wrong time causing the symptoms of the disease.
“Our
study builds on this model and identifies a new mechanism that allows this
relaxation and DUX4 production to occur. Production of DUX4 in muscle cells can
be viewed as a molecular switch. We’ve discovered that the switch that turns on
DUX4 expression can be activated in different ways but the mechanism of muscle
destruction by DUX4 remains the same. Identifying different ways the switch can
be activated is a crucial step toward therapy development because it allows us to
apply multiple and different strategies to prevent activation of the
switch.” Miller said.
Five
percent of FSHD-affected individuals have array lengths, longer than 10 copies
(the threshold for chromatin relaxation), of the DNA sequence in question making
them appear to lack the genetic mutation that normally causes FSHD. However, these unusual individuals lacked
repression of DUX4 code-reading in their skeletal muscle cells because of a
mechanism other than copy number.
“Breakthroughs
in scientific discovery are often achieved by studying individuals with unusual
disease presentations,” Miller said. In a multi-institutional collaborative
effort the researchers identified individuals without the usual FSHD-disease
causing DNA deletion but who still lacked repression of the DUX4 code reading.
Dr.
Rabi Tawil at the University of Rochester made the clinical diagnosis in these
people and established cultures of muscle cells from biopsies. Dr. Richard Lemmers working in van der
Maarel’s laboratory demonstrated that the chromatin structure was relaxed
despite a normal number of repeat units on chromosome 4. With the help of Dr.
Michael Bamshad, UW professor of pediatrics, and
Dr. Deborah Nickerson, UW professor of genome sciences, Dr. Daniel Miller and
his group sequenced and analyzed the protein coding portions of the genomes of
individuals with FSHD caused by this uncommon mechanism.
The researchers discovered that these individuals had causative
mutations in the Structural Maintenance of Chromosomes Hinge Domain 1 gene
located on chromosome 18. Mutations in this gene cause decreased levels of the
SMCHD1 protein and result in relaxation of the chromatin structure surrounding
the muscle cells’ DNA allowing toxic DUX4 to be generated from chromosome 4.
Understanding the FSHD-causing mechanism of SMCHD1 mutations,
Miller said, suggests ideas for therapeutic strategies to suppress the
production of the muscle-damaging DUX4 and for treatments for the more common
forms of FSHD.
This study would not have been possible without the support
of Friends of FSH Research. Friends of FSH Research has sponsored Dr. Daniel
Miller since he began working on FSHD in 2006. Dr Stephen Tapscott leads a
multi-institutional program project to study FSHD mechanisms and pathology. The
NIH funded project includes subprojects by Friends of FSH Research’s sponsored scientists
Dr. Silvere van der Maarel, Dr. Rabi
Tawil, Dr. Galina Filippova and Dr. Daniel Miller and the award of NIH funds
for this project can be largely attributed to preliminary data generated by
Friends of FSH Research’s sponsored projects.
Friends of FSH Research is a 501(3)(c) non-profit
organization whose mission is to
stimulate and fund FSH Muscular Dystrophy research in hopes of finding a
treatment or cure for this progressively, disabling condition. Friends of FSH
Research relies upon donations and their
annual charity gala, learn more or make a donation go to www.fshfriends.org.
