PA) – Researchers at the University of Pennsylvania
School of Medicine have located the “skeleton key,”
a gene that, when damaged, causes the body’s skeletal muscles
and soft connective tissue to undergo a metamorphosis into bone,
progressively locking joints in place and rendering movement impossible.
Identifying the gene that causes fibrodysplasia ossificans progressiva
(FOP), one of the rarest and most disabling genetic conditions known
to humans and a condition that imprisons its childhood victims in
a “second skeleton,” has been the focus at Penn’s
Center for Research in FOP and Related Disorders for the past 15
years. This important discovery is relevant, not only for patients
with FOP, but also for those with more common skeletal conditions.
Senior authors Eileen M. Shore, PhD, and Frederick
S. Kaplan, MD, both from the Penn Department of Orthopaedic
Surgery, and their international consortium of colleagues, report
their findings in the April 23 advanced online edition of Nature
Genetics. “The discovery of the FOP gene is relevant
to every condition that affects the formation of bone and every
condition that affects the formation of the skeleton,” says
The discovery of the FOP gene was the result of painstaking work
by the Penn scientists and their colleagues in the International
FOP Research Consortium over many years. It involved the identification
and clinical examination of multigenerational families, often in
remote regions of the world; genome-wide linkage analysis; identification
of candidate genes; and finally, the DNA sequencing and analysis
of those candidate genes. The team found that FOP is caused by a
mutation of a gene for a receptor called ACVR1 in the bone morphogenetic
Kaplan describes FOP as the “Mount Everest” of genetic
skeletal disorders. His lifelong ambition, as he puts it “is
to conquer the summit of this daunting mountain range and see this
emerging knowledge turned into novel therapies that can dramatically
improve the life of these children. This is nothing less than a
campaign for physical independence and personal freedom for these
kids. If the knowledge helps us to see farther to help others, that
will be great, but this work is for and about the children.”
in Two Million
FOP is one of the rarest conditions known to medicine, found in
only one in 2 million individuals, but, as Kaplan says, quoting
from William Harvey who discovered the circulation of the blood,
“Nature is nowhere accustomed more openly to display her secret
mysteries than in cases where she shows traces of her workings apart
from the beaten path.” Of an estimated 2500 total FOP patients
worldwide, there are approximately 600 known patients, and the FOP
research group at Penn knows nearly all of them. Says Kaplan, “They
are our children, our family.”
Early in life, because of a possible molecular short-circuit in
the wound repair system of the body, tendons, ligaments, and skeletal
muscle begin an inexorable transformation into an armament of bone,
imprisoning its childhood victims in a second skeleton. “FOP
bone is perfectly normal in every way, except it should not be there,”
says Kaplan. “There are no other known examples of one normal
organ system turning into another. It's like a runaway factory for
making bone that just won't stop.”
Children with FOP seem normal at birth, except for telltale malformations
of the great toes that look like congenital bunions. Early in childhood,
painful swellings that are often mistaken for tumors seize the skeletal
muscles and transform them into bone. Eventually, ribbons, sheets,
and plates of bone cross the joints, lock them in place, and render
movement impossible. Attempts to remove the extra bone leads to
explosive growth of new bone. Even the slightest trauma such as
bumps, bruises, childhood immunizations, and injections for dental
work can cause the muscles to turn to bone.
For now, there is no effective prevention or treatment for the molecular
sabotage of FOP. The discovery of the FOP gene and the unique mutation
that causes FOP provides a highly specific target for future drug
development that holds promise for altering not just the symptoms
of the disease, but the disease itself.
Penn Team Builds on Past Findings
The Penn team originally surmised that FOP was caused by a mutation
of a gene in the bone morphogenetic protein (BMP) signaling pathway,
one of the most highly conserved signaling pathways in nature. BMPs
are regulatory proteins involved in the embryonic formation and
post-natal repair of the skeleton.
the FOP gene encodes a BMP receptor called Activin Receptor Type
IA, or ACVR1, one of three known BMP Type I receptors. BMP receptors
are protein switches that help determine the fate of the stem cells
in which they are expressed. The ACVR1 protein is 509 amino acids
long, and in FOP the amino acid histidine is substituted for the
amino acid arginine at amino acid position 206 in all affected individuals.
FOP is the first human genetic disease ascribed to ACVR1. “Our
identification of ACVR1 as a critical regulator of endochondral
bone formation during embryogenesis and in post-natal tissues will
undoubtedly re-focus thinking and stimulate new research directions,”
says Shore. “This discovery will have a major impact on the
study of skeletal biology and regenerative medicine.
“This single amino acid substitution is predicted to change
the sensitivity and activity of the receptor,” continues Shore.
“As is the case for most genes, every cell has two copies
of the ACVR1 gene. In FOP patients, one of the two ACVR1
gene copies harbors a mutation that causes the ACVR1 protein to
be incorrectly made.”
In FOP, the ACVR1 gene is damaged by the substitution of
a single genetic letter at a specific location in the gene. The
single nucleotide substitution changes the meaning of the genetic
message encoded by the ACVR1 gene. “Thus, the substitution
of one genetic letter for another out of six billion genetic letters
in the human genome – the smallest and most precise change
imaginable – is like a molecular terrorist that short circuits
a functioning set of muscles and connective tissues and transforms
them into a second skeleton – in essence turning a light bulb
into an atom bomb,” says Kaplan.
ACVR1 is an important BMP signaling switch in cartilage cells of
the growth plates of growing bones, especially in the hands and
feet, as well as in the cells of skeletal muscle. In previous studies
in chickens and zebrafish, other researchers have found that an
artificially made “trigger happy” copy of the ACVR1
gene (similar, but not identical to the FOP gene mutation) makes
muscle cells behave like bone cells, upregulating BMP4 expression;
downregulating BMP antagonist expression (such as noggin); expanding
cartilage elements in growing bone, eventually inducing extra bone
growth; and stimulating joint fusion - clinical and molecular features
nearly identical to those seen in individuals with FOP.
In the definitive genetic linkage analysis described in the Nature
Genetics paper, which located the FOP gene to a region on chromosome
2, the researchers used a subset of families in whom all affected
individuals had unambiguous features of classic FOP, features that
included typical congenital malformations of the great toes and
a predictable pattern of extra-skeletal bone formation that mimics
the embryonic patterns by which the normal skeleton forms. The researchers
have found that every person with classic FOP has the identical
mutation in the ACVR1 gene.
Computer modeling of the three-dimensional structure of the mutant
ACVR1 protein suggests altered activation of this form of ACVR1.
“Presumably, the FOP mutation causes a molecular short circuit
or promiscuous activation of the receptor, but the detailed molecular
physiology is still being deciphered,” says Kaplan. “Such
knowledge will be essential to develop treatments and an eventual
cure for FOP.”
“To really understand the physiological consequences, we have
begun to develop a genetically engineered mouse with the FOP mutation,”
The ACVR1 gene and protein have been encoded in the molecular
machinery of vertebrate DNA for nearly 400 million years –
long before the earliest dinosaurs appeared on Earth – suggesting
that nature needs to maintain an arginine at codon 206 to support
the normal functions of cells, tissues, and organs. Now it will
be important to develop an animal model with the same mutation in
ACVR1 that is found in people who have FOP. The ACVR1
gene is highly conserved throughout vertebrate evolution, from fish
to mice to humans, but whether or not a mouse will develop FOP remains
to be seen.
“We now know the cause for FOP at the genetic level, and we
expect that it will not be long before we understand the mechanism
at the molecular level,” says Kaplan. “That knowledge
may someday be used, not just for understanding and treating FOP,
but for treating many common disorders that affect the skeleton
– conditions such as non-genetic forms of extra bone growth
that may occur following total hip replacement, head injuries, spinal
cord injuries, sports injuries, blast injuries from war, and even
osteoarthritis and damaged heart valves. Perhaps someday we will
be able to harness the gene mutation that causes the renegade bone
formation in FOP and make bone in a controlled way – for patients
who have severe osteoporosis, for those with severe bone loss from
trauma, for those with fractures that fail to heal or spinal fusions
that are slow to heal, or for those with congenital malformations
of the spine and limbs. We have reached a summit on our epic journey
to understand FOP – knowledge we desperately need to help
the kids and that will likely help many others. We still have a
long way to go, but finally we can see a therapeutic horizon above
the clouds, and the view is promising.”
This research was funded by families and friends of FOP patients
worldwide; the International FOP Association (www.ifopa.org);
and the National Institutes of Health. Co-authors are Meiqi Xu,
George J. Feldman, and David A. Fenstermacher, all from Penn; Matthew
A. Brown, from the Centre for Immunology and Cancer Research, Princess
Alexandria Hospital, Woolloongabba, Queensland, Australia; and the
FOP International Research Consortium.
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