In previous studies, Lee and his colleagues had discovered that a protein known as CRTAP associates with the type of collagen that helps give structure to bone. To learn more about CRTAP's role, Lee and his colleagues produced mice that lacked the CRTAP gene.
They found that without CRTAP, mice developed deformed and brittle bones similar to those of patients with brittle bone disease. In further studies, they found that the CRTAP protein interacts with the enzyme responsible for prolyl 3-hydroxylation of collagen and is required for this process to occur. Without CRTAP, they found, collagen structure in the mice was abnormal, Lee said.
Reasoning that the same mutation might cause brittle bone disease in humans, the researchers next analyzed CRTAP in two families who had brittle bone disease, but lacked the pattern of inheritance commonly associated with the disease. Most forms of brittle bone disease arise from mutations in the genes for the most abundant bone protein, called type I collagen. These mutations are spontaneous and dominant, not inherited from parents. The two families that Lee and his colleagues focused on, in contrast, showed a recessive form of the disease that was inherited. Other researchers had mapped this defect to the chromosomal region that contains the CRTAP gene.
By studying these families, Lee and his colleagues found that partial loss of function of the CRTAP protein caused mild brittle bone disease, and profound loss called a more severe form of the disease. "This was the clincher," said Lee. "We had produced a mouse model of osteoporosis stemming from clear and novel biochemical activity associated with the mutant CRTAP protein. And we had shown that there is an effect on the collagen fibers
Contact: Jennifer Michalowski
Howard Hughes Medical Institute