Research partly supported by the National Institute of Arthritis and Musculoskletal and Skin Diseases has identified a new gene that is linked to the development of osteogenesis imperfecta (OI), a disorder characterized by bones that break easily. The finding, reported in Cell, will have a significant impact on OI diagnosis and should provide more comprehensive genetic counseling for individuals and family members affected by the disease.
Osteogenesis imperfecta is a disorder of collagen: the major protein of the body's connective tissue that provides the framework on which bone and cartilage are built. This research identified a new gene, known as cartilage-associated protein or CRTAP, that when mutated likely prevents fully functional collagen from forming.
The study was a collaborative effort led by Roy Morello, Ph.D., and Brendan Lee, M.D., Ph.D., of Baylor College of Medicine, and an international team of researchers. The research consisted of a chain of important discoveries. First, investigators identified CRTAP when searching for proteins involved with skeletal development. Not sure of its exact function, they then developed a strain of genetically engineered mice that lacked the CRTAP gene. These mice processed collagen abnormally and developed kyphosis (curvature of the spine) and severe osteoporosis resembling the classic features of osteogenesis imperfecta. Subsequent human genetic studies of OI family members revealed that CRTAP mutations were in fact linked to select types of the disease.
Prior to the discovery of CRTAP, osteogenesis imperfecta was largely known to be caused by a dominant genetic mutation in which the OI gene is inherited directly from a parent or by a spontaneously occurring mutation after conception. (This means that only one copy of the gene is needed for the person to have the disease.) However, this research demonstrated that certain forms of OI can be inherited in a recessive manner. (In other words, the CRTAP mutation must be inherited from both parents.)
The CRTAP discovery has swiftly impacted genetic counseling and diagnostic testing for OI. Medical professionals interested in referring patients to be tested for the new recessive form of the disease (as well as the classical types of OI) may consult the Web site of the National Institute of Child Health and Human Development's OI program at https://www.nichd.nih.gov/health/topics/osteogenesisimp/resources/patients or the Baylor Medical Genetics Laboratories at 1-800-411-GENE (4363), Fax: 713-798-6584 (genetictest@bcm.edu).
This research was also supported by the National Institute of Dental and Craniofacial Research, the National Institute of Environmental Health Sciences, the National Institute of Child Health and Human Development, the Baylor College of Medicine Mental Retardation Developmental Disabilities Research Center, the Shriners of North America, the Osteogenesis Imperfecta Foundation and the Bone Diseases Program of Texas.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov. Information on osteoporosis and other bone disorders is available from the NIH Osteoporosis and Related Bone Diseases~National Resource Center; phone toll-free 800-624-BONE (2663), or visit https://www.bones.nih.gov/.
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Morello R, et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 2006;127(2):291-304.