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Date: February 29, 1996 For Release: 5:00 E.S.T. Contact: NIDR Wayne A. Little (301) 496-4261
A study at the National Institutes of Health has linked a mutation in a growth factor gene to a type of dwarfism that is characterized by abnormal development of the limbs and limb joints. The identification of the gene and its critical role in skeletal development could lead to new approaches for repairing cartilage and bone defects and reconstructing joints.
Scientists in the Bone Research Branch at the National Institute of Dental Research identified the structure of the human gene that carries the blueprint for a growth factor called cartilage-derived morphogenetic protein-1, or CDMP-1. The investigators discovered that a mutated version of the gene is present in individuals with a form of dwarfism known as Hunter-Thompson type chondrodysplasia. Affected individuals have shortened and misshapened bones in the lower arms and legs, with the most pronounced disturbances in the joints of the hands and feet. The fingers are very short and the toes are ball-shaped and functionless. The study results are reported in today's issue of Nature Genetics.
"The association of a CDMP-1 gene mutation with Hunter-Thompson chondrodysplasia provides direct evidence that this morphogenetic protein plays a key developmental role at sites of bone growth and joint formation," said Dr. Terrig Thomas, lead author on the paper.
Identification of the human gene opens the door for using recombinant DNA technology to produce CDMP-1 commercially and evaluate its potential for skeletal repair and joint reconstruction. Although the scientists still don't know exactly how the growth factor functions, recent work by study director Dr. Frank Luyten demonstrated that a recombinant form of CDMP-1 led to the formation of cartilage and bone when implanted under the skin of rats.
The discovery of the human gene mutation evolved from recent findings in several laboratories. A mouse strain with short and deformed limbs was found to be caused by a mutation in the mouse equivalent of the CDMP-1. Meanwhile, Dr. Luyten and colleagues at NIH demonstrated that the human gene for CDMP-1 becomes active during fetal development, and is switched on primarily in the cartilaginous portions of developing limb bones and joints. "The Hunter-Thompson cases reported in the literature had abnormalities in the same areas of the body in which we observed CDMP-1 gene activity, " said Dr. Luyten. "Coupled with the mouse data, this human disorder became a prime candidate for a defect in CDMP-1."
The investigators determined the DNA sequence of the CDMP-1 gene and found an extra piece of DNA inserted into the gene of those affected with Hunter-Thompson chondrodysplasia. According to Dr. Luyten and Dr. Thomas, the mutation most likely results in a faulty protein that can't carry out its role in the normal development of limbs and joints.
CDMP-1 is a growth regulator that is a member of the transforming growth factor-beta (TGF-beta) superfamily of proteins, which have many diverse functions in normal development across the animal kingdom. Despite the fact that Hunter-Thompson chondrodysplasia is quite rare and has been documented only in a few families from isolated communities, this study is the first example of a human disorder attributable to a mutation in one of these proteins.
The investigators on this study were Drs. J. Terrig Thomas, Keming Lin, Maithily Nandedkar, and Frank Luyten of the Bone Research Branch, National Institute of Dental Research, National Institutes of Health; Dr. Mauricio Camargo of the University of Antioquia, Medellin, Columbia; and Dr. Jaroslav Cervenka of the University of Minnesota School of Dentistry. Blood samples from affected individuals and their families, obtained in collaboration with scientists from Medellin, Columbia, were used to isolate the DNA.