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New collagen-modifying osteogenesis imperfecta gene discovered
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Collaborations between investigators at the National Institutes of Health and other U.S. institutions has led to the discovery of the third gene in a sequence that accounts for previously unexplained forms of osteogenesis imperfecta.
Most types of osteogenesis imperfecta (OI), also known as brittle bone disease, that have been identified relate to a dominant mutation in collagen. The type involving the newly discovered Cyclophilin B gene corresponds to a recessive trait, and individuals need two defective copies of the Cyclophilin B gene to develop OI.
The gene is needed to make the protein Cyclophilin B, part of a complex that modifies collagen by folding it into a precise molecular configuration before it is secreted from cells.
New collagen formation
Findings from this study suggest that Cyclophilin B is not solely involved in collagen folding, and that perhaps an unknown protein must also be involved in the process, according to a press release from the National Institutes of Health (NIH)/National Institute of Child Health and Human Development (NICHD).
“The discovery provides insight into a previously undescribed form of OI,” Alan E. Guttmacher, MD, acting director of NIH’s Eunice Kennedy Shriver NICHD, stated in the release. “The advance also provides new information on how collagen folds during normal bone formation, which may lead to greater understanding of other bone disorders.”
Recessive mutation
The study, which appears in the New England Journal of Medicine, began after investigators discovered two siblings who developed OI, but lacked the classic sign of shortened upper limbs. The condition, called rhizomelia, occurs in children with recessive gene mutations for collagen proteins, namely cartilage associated protein or CRTAP and prolyl 3-hydroxylase 1 (P3H1).
Joan Marini, MD, PhD, chief of NICHD’s Bone and Extracellular Matrix Branch, and colleagues previously discovered the CRTAP and P3H1 gene mutations, which can result in severe forms of OI. Patients with CRTAP mutations have all died in childhood, and mutations in P3H1 are sometimes fatal in early life, according to the release.
Marini noted that additional research may help determine why these siblings developed OI despite having seemingly normal collagen folding in conjunction with the recessive Cyclophilin B gene mutation.
- Reference:
Barnes AM, Carter EM, Cabral WA, et al. Lack of Cyclophilin B in osteogenesis imperfecta with normal collagen folding. N Engl J Med. 2010. E-pub ahead of print.