Researchers say they have found the genetic glitch behind a devastating disease that turns muscle to bone, eventually turning victims nearly into living “statues.”

The rare condition, affecting an estimated 2,500 people worldwide, progressively converts more and more muscle, tendons and ligaments into bone. Eventually joints are locked into place, making movement impossible.

The researchers, at the University of Pennsylvania School of Medicine, said they have been working for 15 years on identifying the gene, dubbed the “skeleton key.”

The discovery is relevant not only for patients with the illness, called fibrodysplasia ossificans progressiva, or FOP, but for others with more common skeletal conditions, they said.

Eileen Shore and Frederick Kaplan of the university, along with colleagues from other institutions, reported the findings in the April 23 advance online edition of the research journal Nature Genetics.

The mutation, they found, involves a gene encoding a molecule called ACVR1.

The disease begins in childhood, when tendons, ligaments, and skeletal muscle begin an inexorable transformation into an armament of bone. This bone “is perfectly normal in every way, except it should not be there,” Kaplan. “There are no other known examples of one normal organ system turning into another.”

Victims seem normal at birth, except for telltale malformations of the great toes. Early in childhood, painful swellings often mistaken for tumors seize the skeletal muscles and turn them into bone.

Eventually, ribbons, sheets, and plates of bone cross the joints and lock them into place. Surgically removing the extra bone just causes it to grow back faster. Slight traumas such as bumps, bruises and injections can stimulate further transformation into bone.

Victims often die, typically in their 40s, from complications related to difficulty breathing as the bone restricts the space available for their lungs to move. There is no effective treatment, but the researchers hope the gene’s discovery will change that.

The condition, they said, results from a defect in a natural chain of molecular events called the bone morphogenetic protein signaling pathway, involved in the formation and repair of the skeleton.

The molecule encoded by the newfound gene functions as a sort of “switch,” the scientists explained. The molecule appears in certain stem cells, immature cells that can develop into a variety of different cell types for diverse organs.

The molecule consists of 509 subunits, called amino acids, of which one is defective in the condition, the researchers said: an amino acid known as histidine appears where another one, arginine, should be.

This change somehow affects the activity of the “switch,” they explained, though understanding exactly how requires further study.

“As is the case for most genes, every cell has two copies of the ACVR1 gene,” Shore said. In patients with the disease, one of the two harbors the mutation, which produces a defective version of the molecule.

Whereas the defect in the molecule consists of a substituted amino acid, the defect in the gene itself—which produces that molecule—is a substituted “letter” of genetic code, called a nucleotide.

“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,” said Kaplan.

ABOUT THE AUTHOR

Science writer Jack Lucentini is founder and editor of the World Science science news webzine. He has worked as a staff writer at three daily newspapers, and as a freelance science writer for a range of publications including The Washington Post, Discover magazine and The Scientist magazine. He earned his bachelor's degree at Oberlin College in Oberlin, Ohio in 1993.