Penn researchers discover gene that creates "second skeleton" bone disorder

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."