A mysterious disease that causes skin and muscle tissue to turn into bone is becoming a little less mysterious, as Penn researchers have found the gene that causes the disorder.
Penn Orthopedic Surgery Professors Frederick Kaplan and Eileen Shore have co-authored a study published earlier this month on the rare disease called Progressive Osseous Heteroplasia.
POH -- which was first discovered at Penn -- is a crippling disease that turns skin and muscle into bone, resulting in Rice Krispies-like dots of bone that erupt through the skin and eventually fuse with the skeletal structure.
The discovery of the genetic basis for POH is the first step toward finding a cure for the disorder.
Kaplan, a physician who came to Penn in 1976, became interested in children's bone disorders in 1990. After studying patients with a disease known as fibrodysplasia ossificans progressiva, which causes tumor-like growths of cartilage and bone with the slightest injury, he noticed patterns of unusual differences between some of the patients and wondered if all these patients really had FOP.
The observation led the researchers to diagnose their first patient with POH and then publish their initial findings on the disease in 1994. Research progressed slowly until they received a packet of information and X-rays of a patient diagnosed with POH from a doctor at Brown University.
A few days later, Kaplan received another packet from an endocrinologist at Brown who said he had a patient with Albright's, a disease similar to POH caused by a mutation in the GNAS1 gene, which causes a reduced response to some hormones.
"I was looking at these two packets of information, and all of a sudden, I realized, 'My God, these are about the same patient,'" Kaplan said. "Then I asked myself, 'Why would a child have two extremely rare diseases?' It didn't dawn on us until we saw [the patient] the next week."
What Kaplan and Shore discovered was that the identical mutation occurred in both POH and Albright's.
"The puzzle was why the same mutation could cause two different rare diseases," Kaplan said.
Most of the human body's cells have two copies, or alleles, of any given gene -- one passed on by the mother and one by the father. But one allele is usually deactivated in a process called "genetic imprinting."
"In Albright's, the genetic cause has been known for some time -- the father's gene is imprinted and the mother's mutant gene is activated in hormonal cells," Shore said.
It was not until the POH team came across a family from Australia that had been diagnosed with both POH and Albright's that they finally understood how the two diseases could exist simultaneously.
The father of the family carried the mutant GNAS1 gene and had passed it along to his four daughters, who were diagnosed with POH. Those daughters, in turn, had children -- but the children that received the mutant gene had Albright's instead of POH.
"This family was the key in realizing the main difference between Albright's and POH," said Shore. "With Albright's, the defective gene is received from the mother, but with POH it is paternally transmitted."
The hypothesis is that, while hormonal cells depend on the mother's allele, at some point during development the father's allele is responsible for determining which cells become bone and which cells do not.
Furthermore, the evidence suggests that unless the father's copy of the GNAS1 gene functions, skin, fat and muscle cells will revert to their default bone state.
Discovering exactly how the GNAS1 gene prevents these cells from turning into bone will do more than help patients who have POH -- it will allow doctors to take skin and fat cells and turn them into bone to repair defects.
"Discovering the gene is not enough. It's a great start, but [POH research] will be a failure if we can't turn it into a treatment," Kaplan said.
Kaplan also added that he would "feel terrible if at the end of my career I can't say that I've done anything to help these wonderful children. We need to do more for the next generation than just giving them wheelchairs."
