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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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