Researchers at the National Institutes of Health have discovered that a previously unexplained fatal form of Osteogenesis Imperfecta, a disorder that weakens bones and which may cause frequent fractures, results from a genetic defect in a protein involved in the production of collagen.
The study appears in the December 28 New England Journal of Medicine.
According to the study, the affected gene contains the information for cartilage associated protein, or CRTAP. The function of CRTAP is not well understood, but it is known to be part of a complex of proteins involved in the chemical transformation of collagen from simple protein chains into its final form.
The well-known forms of Osteogenesis Imperfecta (OI) result from a defect in the genes for type I collagen, which serves as a kind of molecular scaffolding that holds together bone, tendons, skin and other tissues. The collagen defects result from dominant mutations, requiring only one copy of a mutant gene to cause bone disease.
The NIH researchers discovered that mutations in the CRTAP gene accounted for a recessive form of the disorder, requiring two copies of the affected gene to show a particular trait.
The NIH team was led by Joan Marini, M.D., Ph.D., Chief of NIH's Bone and Extracellular Matrix Branch and was assisted by colleagues at other institutions.
"This discovery provides a basis for counseling families that have lost a child to this previously unexplained form of Osteogenesis Imperfecta," said Duane Alexander, Director of the NIH institute that conducted the study, the National Institute of Child Health and Human Development.
"It also offers insight into a crucial step needed in the formation of bone and other tissues."
Dr. Marini explained that from 10 to 15 percent of OI patients do not have a mutation in one of the collagen genes known to cause the disorder. She noted that researchers couldn't explain these cases, and began searching for possible causes.
"The hypothesis was that there must be one or more recessive genes causing something that looked like OI," she said.
The first clue came when colleagues Roy Morello Ph.D., and Brendan Lee, M.D., Ph.D. also authors of the current paper, developed a laboratory mouse that lacked functional copies of CRTAP.
Although there is no treatment for the disorder, the finding can allow OI experts to test families who have lost a child to OI for the presence of the recessive CRTAP gene. Couples who have lost a child to this form of OI could be apprised of their risk for conceiving another child with the disorder.
Similarly, siblings of children affected by the recessive CRTAP gene can also be counseled about their likelihood of carrying the gene.
The researchers have already tested the siblings of the infant who died 15 years ago. Dr. Marini said that she and her colleagues are investigating whether additional forms of OI might be caused by other recessive genes.
Dr. Marini said that the discovery of CRTAP's involvement with OI is exciting to researchers in the bone and genetics fields because it opens a new and unanticipated field of bone biology related to osteoporosis.
“The NIH team is now working to understand the role of this collagen-modification complex in normal bone development. Since CRTAP protein occurs elsewhere in the body, it may play an important role in the development of other tissues”, Dr. Marini added.