Spring 2018

Clues to a Rare Disease

Fish could unlock the mystery of ‘Stone Man Syndrome.’

By David Levin

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Figures D through I show genetically modified zebrafish, with bone appearing in soft tissue where it normally would not exist. Figures A through C show wild zebrafish without the bone. Photo: LaBonty M, Pray N, and Yelick PC.

The symptoms start small. A bruise becomes stiff and sore; a lump forms deep in the flesh beneath it. Within weeks, what was once pliable tissue turns to bone.

Fibrodysplasia Ossificans Progressiva (FOP), or “Stone Man Syndrome,” is an exceedingly rare disease that affects roughly one in every two million people, caused by a single genetic mutation. Over years, it causes a loss of mobility, limited speech, and eventually, the inability to breathe as extra bone fuses the ribs and constricts movement of the lungs.

Until recently, the disease has been incredibly hard to study—even the act of taking tissue samples from patients can trigger explosive bone formation in the injured area. But new work at Tufts School of Dental Medicine may offer a novel way to approach FOP. Pamela Yelick, professor and director of the division of craniofacial and molecular genetics, and graduate student Melissa LaBonty, have developed a method to recreate the disease in zebrafish.

“The zebrafish genome had been sequenced and found to display significant similarities to the human genome,” said Yelick. “When the gene mutation for FOP was identified, we realized that we had already been studying that gene.”

The mutation that causes FOP essentially flips a molecular “switch” that is responsible for triggering bone growth. Normally, that switch activates only in areas of the body where bone needs to grow. In FOP patients, however, it turns on in cells where it doesn’t belong, causing bone to grow out of control in muscle and connective tissue.

Replicating FOP in zebrafish requires more than just adding a mutation to its DNA, LaBonty said. When the researchers tried that, the mutant fish invariably died fewer than three days after hatching. Instead, they developed a way to turn on the faulty gene gradually by making it sensitive to heat. “Basically, you raise the fish without the mutant protein being activated, and then when you want to turn it on, you just increase the temperature of the water in their tank,” LaBonty said. By activating the gene only during short periods of the day, the researchers approximated the human disease.

If researchers can use this model to understand better how the disease works on a genetic and molecular level, LaBonty said, it may be possible to throw a wrench in its works, or stop the mutant genes from being expressed in the first place.

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