Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Penn researchers discover gene that creates second skeleton

25.04.2006
Pinpointing cause of fibrodysplasia ossificans progressiva (FOP) will accelerate development of treatments for FOP and common bone disorders

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 Kaplan.

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 protein-signaling pathway.

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."

One 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.

Indeed, 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.

Looking Forward

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," notes Shore.

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."

Karen Kreeger | EurekAlert!
Further information:
http://www.ifopa.org
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht Researchers reveal new details on aged brain, Alzheimer's and dementia
21.11.2017 | Allen Institute

nachricht Nanoparticles help with malaria diagnosis – new rapid test in development
21.11.2017 | Fraunhofer-Institut für Silicatforschung ISC

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Nanoparticles help with malaria diagnosis – new rapid test in development

The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.

Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

From Hannover around the world and to the Mars: LZH delivers laser for ExoMars 2020

21.11.2017 | Physics and Astronomy

Borophene shines alone as 2-D plasmonic material

21.11.2017 | Materials Sciences

Penn study identifies new malaria parasites in wild bonobos

21.11.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>