Researchers find gene mutation that turns skin and other tissue into bone

(Philadelphia, 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 Osteodystrophy.

"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 of aging.

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.

# # #



Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $405 million awarded in the 2017 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; Penn Wissahickon Hospice; and Pennsylvania Hospital – the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine, and Princeton House Behavioral Health, a leading provider of highly skilled and compassionate behavioral healthcare.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2017, Penn Medicine provided $500 million to benefit our community.

Share This Page: