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November 10, 2000
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Hopkins Researcher Finds Bone Disease and Growth Defect May Have Common Genetic Basis

An examination of two rare, very different and hereditary bone disorders has revealed clues about the common genetic switches controlling normal bone development, according to new research guided by Johns Hopkins Children’s Center endocrinologist Michael Levine, M.D.

In the November issue of the Journal of Bone and Mineral Research, Levine’s group describes two girls diagnosed with both Albright’s hereditary osteodystrophy (AHO) and progressive osseous heteroplasia (POH). They found that abnormal bone formation was more severe in the two girls than in patients with AHO alone and that the girls’ symptoms were more typical of POH, implying that the developmental and biochemical pathways leading to each condition intersect at some point along the way.

Both girls had severely depressed levels of an important protein called Gs-alpha that helps cells adjust their internal energy use in accordance with the body’s needs, suggesting that metabolic pathways using Gs-alpha are the collective culprit behind AHO and POH. How mutant changes in these pathways lead to the development of bone in soft tissues remains unknown, Levine says, but researchers now know where to look.

Levine’s group studied red blood cells from two girls, ages 7 and 10, and analyzed the many proteins that swim inside or on the surface of cell membranes. Using antibodies to selectively hunt down Gs-alpha and bind to it, they compared the concentrations of Gs-alpha in the red blood cells with that of normal red blood cells. In both girls, red blood cells contained about half as much Gs-alpha as normal red blood cells.

A gene, GNAS1, provides the DNA blueprint for Gs-alpha, a protein that plays a critical role in making sure a cell can respond to its external environment. Part of an elegantly complex metabolic system called a signal transduction pathway, normal levels of Gs-alpha make sure that cells can respond to hormones by changing which genes are turned on and off, as well as how fast many proteins work.

Patients diagnosed with progressive osseous heteroplasia develop spontaneous bone fragments under the skin and deep inside their bodies. The fragments can be as large as rice grains and often cause acute pain by pressing against nearby nerve cells. The lesions caused by POH can be identified, leading to diagnosis soon after birth. Albright hereditary osteodystrophy is characterized by short stature, obesity, relatively short fingers and, often, endocrine problems. AHO is usually diagnosed during childhood. Although the actual incidence of AHO and POH in the population is unknown, Levine estimates one of every 100,000 individuals is affected by either of the disorders. The two diseases rarely occur together in a single person.

Researchers from the Shriners Hospital for Children in St. Louis, Mo., and the Washington University School of Medicine in St. Louis, Mo., the University of Pennsylvania School of Medicine in Philadelphia, and the Shriners Hospital in Salt Lake City, Utah, contributed to the report. Support for the research came from grants supplied by the Shriners Hospital for Children in St. Louis, The Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund, The International Fibrodysplasia Ossificans Progressiva Association, the Progressive Osseus Heteroplasia Association, the New Jersey Association of Student Councils, the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine, and the National Institutes of Health.


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