Mutation Causes Some Cases of Brittle Bone Disease

Brendan Lee, MD, Ph.D.
Howard Hughes Medical Institute and Baylor College of Medicine
P01ES011253

Osteogenesis imperfecta (OI), also known as brittle bone disease, is a group of genetic bone disorders resulting in frequent fractures. It is caused by structural changes in collagen proteins. A newly identified gene mutation helps explain a subset of cases of OI whose origin had until now remained mysterious. Brendan Lee, an NIEHS-supported researcher at the Baylor College of Medicine and the Howard Hughes Medical Institute identified the mutation, which is responsible for up to 15 percent of OI cases. The mutation prevents collagen proteins from being properly modified after they are produced.

Immediately after collagen is produced, it undergoes several biochemical modifications to transform it into functional fibers. One of these modifications is the addition of a hydroxyl group to one amino acid along the thousand amino acid chain of the collagen protein fiber. Using transgenic mice, Lee and his colleagues discovered that cartilage-associated protein (CRTAP) interacts with the enzyme responsible for the hydroxylation of the collagen protein. The mutation they discovered in CRTAP prevents this interaction and thus, prevents the protein modification resulting in damaged collagen and poor bone formation.

The researchers then reasoned that the same mutation might cause OI in humans. They focused on two families with a recessive form of OI that other researchers had mapped to the same chromosomal region containing the CRTAP gene. They found that a partial loss of CRTAP function caused OI and that a complete loss caused an even more severe form of the disease.

These findings could have important diagnostic implications especially surrounding suspected child abuse cases. Until now, the only known genetic cause of OI was a structural mutation in type I collagen. According to Lee, this finding "adds a new dimension in terms of DNA testing." It also may also offer clues to the causes of connective tissue diseases that affect other parts of the body and gives insight into the basic mechanism of collagen formation.

Citation: Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, Castagnola P, Rauch F, Glorieux FH, Vranka J, Bachinger HP, Pace JM, Schwarze U, Byers PH, Weis M, Fernandes RJ, Eyre DR, Yao Z, Boyce BF, Lee B. CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006 Oct 20;127(2):291-304.