Second Gene Discovered for Form of Brittle Bone Disease

Normal bone is a dense, strong matrix. National Osteoporosis Foundation

Hot on the heels of the discovery of a gene involved in a previously unexplained form of osteogenesis imperfecta (OI), researchers have found another genetic defect involved in the bone-weakening disorder.

OI is an uncommon disorder that occurs in one out of 15,000 to 20,000 births. About 85% of all cases are caused by dominant mutations in the two genes for type I collagen, an important building block for bone. These mutations are called "dominant" because inheriting just one copy of the mutated gene will cause the disorder. Scientists long suspected that other causes of the disease existed, however, because about 15% of people affected with the disorder didn't have mutations in their collagen genes.

Last year, Dr. Joan Marini of NIH's National Institute of Child Health and Human Development (NICHD) and her colleagues reported that a defect in the gene for cartilage-associated protein (CRTAP) can cause a lethal form of OI. CRTAP is one of the proteins that modify newly made collagen into its final form before it is secreted from cells to become part of the structure of bone. The form of OI linked to CRTAP is recessive, meaning that one copy of the mutated gene will not cause the disorder; only people who carry two copies are affected.

In the February 4, 2007, online edition of Nature Genetics, Marini and her colleagues described their study of five children with unexplained causes for their OI. Of the five, three had a lethal form of OI; the other two had a nonfatal form with severely abnormal bone development. Dr. Marini and her team found that the children all had defects in the gene coding for a protein called prolyl 3-hydroxylase 1 (P3H1). P3H1 is part of the same complex of proteins as CRTAP. The proteins produced by the two genes normally work together to modify collagen.

Defects in CRTAP and P3H1 together appear to account for most cases of recessive OI. The infants and children described in Marini's studies have two defective copies of either CRTAP or P3H1 so that almost no protein is produced, resulting in defective bone formation. Patients who have a loss of function of either CRTAP or P3H1 will develop severe OI, but such mutations in P3H1 aren't always fatal, as they are in people without a functioning gene for CRTAP.

“This discovery has completely changed the ability to diagnose babies with lethal and severe osteogenesis imperfecta,” Marini said. Her lab has already performed a genetic test confirming that a child's unknown disease was recessive OI.

Although there is no treatment for OI, this finding could help the families of people with the disorder and their doctors to understand the risk of conceiving children with OI. Medical professionals interested in referring patients to NIH to be tested for OI types can consult NICHD's OI program web site at http://www.oiprogram.nichd.nih.gov/.