Researchers find gene mutation that turns skin and
other tissue into bone
PA) -- Researchers at the University of Pennsylvania
School of Medicine have found a gene mutation that
causes a rare hereditary disorder in which skin, muscle
and fat tissue gradually are replaced by bone. In this
disease, known as Progressive Osseous Heteroplasia (POH),
the mutation passes on via the father. Identification
of the mutated gene, an important step toward a possible
cure for POH, also has implications for a number of
potential medical treatments that require knowledge
of how the body makes different tissues. The study will
be published in the January 10th issue of the New England
Journal of Medicine.
"We hope to eventually stop this renegade bone
formation in those who have a damaged copy of the gene,"
said Frederick S. Kaplan, MD, co-author of the
study and professor of Orthopaedic Molecular Medicine
and Chief of Metabolic Bone Diseases and Molecular Medicine
at the Hospital of the University of Pennsylvania. "Further
research will attempt to increase our knowledge of the
functions of the gene, called GNAS1, as well as the
molecules that interact with it. That knowledge may
eventually allow us to turn-on bone formation in more
common conditions where it is sluggish or doesn't happen
at all," added Kaplan. "It may also give us
an important clue of how to engineer unwanted fat into
useful bone tissue and place it where it is needed."
POH was originally characterized and named in 1994 by
Kaplan and colleagues. The insight into where to look
for the mutation came from a surprisingly common factor
between POH and another disease, Albright Hereditary
"Ossification of skin is a very rare occurrence,"
explained Eileen M. Shore, PhD, a professor and
researcher in Penn's Department of Orthopaedic Surgery
and the lead author of the study. "However, when
we started looking for the gene that causes POH, we
were well aware of Albright Hereditary Osteodystrophy,
which has been associated with small, limited patches
of skin ossification."
Albright Hereditary Osteodystrophy is a rare disorder
in which the major symptoms are caused by a reduced
response to some hormones. This is caused by a mutation
that silences or 'inactivates' the GNAS1 gene, so that
it no longer works and information from the hormones
is blocked. In inherited cases of Albright Hereditary
Osteodystrophy, a child typically inherits a mutation
from the mother. In comparing the diseases, the Penn
researchers and their colleagues discovered that POH
is also caused by an inactivating mutation of GNAS1
-- but this time from the father's genetic contribution.
Most of the cells of the body have two copies, or 'alleles,'
of any given gene -- one inherited from the father and
one from the mother. For some genes, the cell can distinguish
the parental origin of an allele, a phenomenon called
imprinting. "Not all genes are imprinted,"
said Shore. "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."
There are many implications of the finding. Many researchers
are currently trying to develop a variety of medical
treatments that involve turning precursor cells called
stem cells into different types of body tissue. Stem
cells can become skin cells or bone cells or brain cells
as well as many other types of cell. These treatments
aim to replace or repair specific types of tissue that
have been damaged by injury or simply by the effects
GNAS1 is known to produce a protein that is associated
with receptors existing in many different cells. Receptors
are important components of the transmission of information
from one cell to another, and it is this cell-to-cell
signaling process that often plays a powerful role in
determining which cells develop into what tissue. This
is obviously crucial during growth and development,
but is also important for the maintenance and health
of an adult.
This finding makes it clear that silencing the paternal
allele of GNAS1 causes cells to turn into bone that
would not do so otherwise. "The copy of the gene
(GNAS1) that we receive from our fathers has the specific
responsibility of preventing our skin, our fat, and
our skeletal muscles from becoming bone," explained
Kaplan. "Why our body has the opportunity to turn
those tissues into bone in the first place is the greatest
mystery of all."
Collaborators on this research include Jaimo Ahn,
PhD, Ming Li, and Meiqi Xu of the
Penn Department of Orthopaedic Surgery; Michael A.
Zasloff, MD, PhD, of the Penn Department of Genetics;
Suzanne Jan de Beur, MD, and Michael A. Levine, MD,
of the Departments of Medicine and Pediatrics, respectively,
at Johns Hopkins University School of Medicine; R.J.
McKinlay Gardner, MB, of the Royal Children's Hospital
in Melbourne, Australia; and Michael P. Whyte, MD, of
the Center for Metabolic Bone Disease and Molecular
Research at Washington University School of Medicine.
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