Mullins' participation in the study was serendipitous, says Shore. Mullins studies BMP signaling in zebrafish, and in these animals BMP plays many roles, including establishing an organism's basic body plan. Mullins' long time interest was a particular gene critical to this process, called Alk8. As it turns out, Alk8 is the zebrafish equivalent of human ACVR1.

Importantly, Mullins had already established a zebrafish genetic line that fails to express Alk8. When the team inserted the gene for human ACVR1 into those fish, their normal body plan was restored. But, when they used the FOP mutation instead, the effect was one of overcompensation

"The FOP form of ACVR1 causes too much BMP expression and we get a hyper-ventralized embryo, too much cell development in the tail region of the fish," Shore explains. "So this confirmed our cell culture studies showing the mutant ACVR1 an activating mutation."

Colleagues at the Max Planck Institute for Molecular Genetics in Berlin, Germany, conducted additional experiments demonstrating that the FOP form of ACVR1 can also enhance cartilage cell differentiation. In the presence of the mutation, mild activation of cartilage development was observed to occur without activation by BMP like a leaky faucet, but could be additionally stimulated by BMP, the fully turned-on faucet.

People with FOP have a mostly normal skeleton and no evidence of extra-skeletal bone at birth; after birth it can be several years before the disease develops, forming extra-skeletal bone either spontaneously or as a result of trauma. The bone formation then progresses in a series of periodic episodes. The current study suggests this periodic progression may occur because the FOP mutation does not turn the ACVR1 faucet on all the way.

"These studies are a good beginning at getting a grasp on what the mutation is and how it is affecting BMP signaling in the cells," says Shore. "But there's a lot more to be understood."

Source: University of Pennsylvania School of Medicine