A team of researchers has identified a new genetic mutation responsible for osteogenesis imperfecta (OI), a condition that makes bones much more likely to break, according to a study published today in the journal Cell.
Victims may experience just a few fractures in a lifetime or several hundred beginning before birth. The number of Americans affected is unknown, but estimates range from 20,000 to 50,000. While the study is an important early step in the search for a cure, its immediate effect may be to exonerate an expanded group of parents whose children frequently appear in emergency rooms with unexplained fractures, and who may be accused of child abuse.
The study was led by Brendan Lee, M.D., Ph.D., associate professor of Molecular and Human Genetics at the Baylor College of Medicine. Brendan Boyce, M.D. professor of Pathology at the University of Rochester Medical Center, added expertise to the large, international research team in the analysis of skeletal defects caused by lack of effective function in the newly discovered gene.
Previously, OI was known only as a genetic disorder in the formation of collagen fibers, the protein framework of which bone and cartilage are built. People with OI were known to have a faulty gene that instructed their bodies to make either too little or weak collagen because of defects or mutations in one of the collagen genes, of which there are more than 20. The current study found a new gene, that when mutated, reduces the ability of a protein involved in collagen formation, called CRTAP (cartilage-associated protein), to guide collagen production as it forms the proper framework of bone.
"The study is important because it clarifies a new mechanism by which the OI can occur and makes possible new tests to identify affected children and provide them with added medical support," Boyce said. "There may be up to 15 percent of children with Brittle Bone Disease who have mutations related to the new gene. Although the number of affected children is small, the demonstration that they have an inherited form of OI could have a major impact on their future health and quality of life."
In the study, mice were genetically engineered by the Baylor team with the CRTAP gene removed, and then monitored for signs of abnormalities. Results showed that the mice were unable to properly line up the fibers that make up collagen using an enzyme called 3-prolyl hydroxylase, which they determined needs to bind to CRTAP for it to function normally. As a result of the loss of normal 3-prolyl hydroxylase function, the cells that build bone (osteoblasts) were found to make thicker collagen fibers, but fewer of them, resulting in weaker bone.
Boyce and his group in the Center for Musculoskeletal Research at the Medical Center characterized the skeletal abnormalities in the genetically engineered mice and carried out studies of bone cells from the mice as well as detailed microscopic analysis of their bones. They found that, without this key gene, mice developed osteoporosis due to defects in their osteoblasts. Another team working at McGill University in Montreal identified human patients who had OI due to mutations in CRTAP, demonstrating for the first time that CRTAP has an essential function in humans.
In addition, the findings of the current study provide the first proof that osteogenesis imperfecta can be inherited in a recessive manner. Previously, the genes known to be involved in OI were dominant, meaning that if you had a defect in the gene in your chromosome, you developed the disease. That left open the possibility that the mutation causing OI was spontaneous, that something went wrong for the first time in the gene of the person developing it, and not inherited from parents.
The newly discovered gene however is a recessive trait, signifying that the disease can be passed down generation to generation, with recessive forms accounting for recurrence. When each parent has one mutated gene and one normal gene, they have one-in-four chance of having a child with osteogenesis imperfecta.
Funding for the research came from the National Institutes of Health, the Baylor College of Medicine Developmental Disabilities Research Center, and the Shriners of North America. Others institutes participating were the Istituto Nazionale per la Ricerca sul Cancro in Genova, Italy, The Shriners Hospital for Children in Oregon, McGill University in Montreal and The University of Washington in Seattle.
"Beyond OI, there may be other connective tissue disorders caused by mutations in genes associated with 3-prolyl hydroxylation, a process that occurs in many types of tissues," Boyce said. "Current treatment for OI does not cure the disease and is designed to reduce the risk of fracture. Only through a better understanding of the disease at the genetic and protein level will we be able to someday offer something better."
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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