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."
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.
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."
Flow of cerebrospinal fluid regulates neural stem cell division
22.05.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Chemists at FAU successfully demonstrate imine hydrogenation with inexpensive main group metal
22.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.
The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...
Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.
Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...
A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.
Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
18.05.2018 | Power and Electrical Engineering
18.05.2018 | Information Technology
18.05.2018 | Information Technology