Solving the Mystery of Extra Bone

Solving the Mysteries of Extra Bone

The Story of Progressive Osseous Heteroplasia, sister disease to FOP

By Sharon Kantanie

Over a five year period (1989-1994), Dr. Frederick Kaplan and his Colleagues examined more than 126 individuals with a rare disease called fibrodysplasia ossificans progressiva, or FOP. But there were also those patients who, despite having a preliminary diagnosis of FOP by the referring physician, didn’t quite fit the mold. In fact, the unique observation of bone formation within the skin during childhood followed by progressive heterotopic ossification of skin, subcutaneous fat, deep connective tissue and muscle didn’t fit any known condition.

In 1994, Dr. Kaplan and his colleagues gave the condition a name, progressive osseous heteroplasia (POH). Since then, the team at the University of Pennsylvania, headed by Drs. Eileen Shore and Fred Kaplan, along with collaborators at Washington University and Johns Hopkins University, have diligently looked for answers to the exceedingly rare condition, which in many ways is a sister condition to FOP. POH can be as disabling as FOP if bone formation is extensive in its distribution.

In 1998, in a remarkable and unexpected discovery, the POH collaborative research group discovered the damaged gene responsible for POH. Many defective genes are discovered by identifying the gene in multiple generations. Only thirty patients were known at the time, so this approach was not available to the Shore-Kaplan team. That left the candidate gene approach—developing a best guess about the location of the gene and then testing it out in lab research. It was an approach that paid off for POH. The POH gene was discovered serendipitiously after seeing several patients whose symptoms provided a clue to a plausible candidate gene. When that candidate gene was examined, changes in the DNA sequence of the gene were found. Several of these changes could be immediately recognized as causing the production of a non-functional protein.

GNAS1, the gene identified for POH apparently encodes a protein located on the inside of the cell membrane in nearly every cell in the body. Early indications are that the Gs-alpha protein normally acts as an inhibitor of bone formation in soft connective tissue (skin, fat, and skeletal muscle). When the G-protein relay switch is broken, the inhibition ceases, and the cell becomes a bone cell by default.

As Dr. Kaplan states, "The discovery of the POH gene is an extremely important development in bone biology and of paramount importance for understanding the earliest cellular and molecular pathways in bone formation. Identification of the gene that causes POH has profound implications for developing treatments for patients with POH and FOP and also for many more who have common diseases of bone formation, such as those who have bone formation in their heart valves."

In fact, POH may be more closely related to several other genetic disorders than previously recognized, forming the extreme end of a spectrum of clinically distinct but genetically related conditions.This brings us to the latest discovery about POH, a discovery reported by Dr. Eileen Shore and colleagues in the January 10, 2002 issue of The New England Journal of Medicine.

Most of the cells in our bodies have two copies of a gene—one inherited from our mother, and one from our father. For some genes, the cell can distinguish the parental origin, a phenomenom known as imprinting. As Eileen Shore explains, "Not all genes are imprinted, but the imprinted genes that have so far been identified have frequently been associated with activities affecting cell growth and development. The molecular basis of how imprinting occurs and is regulated is just starting to be understood."

Curiously, another disease is caused by a mutation in the GNAS1 gene: this disease, which is typically associated with changes in hormone response of specific cells but also can cause minimal ossification of the skin, comes from a mutation that is usually inherited from the mother. By contrast, the POH research team discovered that the POH mutation is inherited from the father’s side. At least part of the mystery, what the gene is and that the effect of mutations in the gene is directed by the inheritance pattern, is solved. But there is still a lot to learn. For example, not all patients with similar mutations in GNAS1 seem to develop POH, suggesting that the genetic process may involve a combination of factors. And Eileen Shore points out that "in POH, as in FOP, not every cell in the body develops into bone, therefore the identity of the bone forming cells will be important to discover in our search for treatments." As Dr. Frederick Kaplan notes, "Why our body has the opportunity to turn those tissues into bone in the first place is the greatest mystery of all."

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