Clinical picture of new forms of brittle bone disease

HOUSTON -- (December 28, 2006) -- A mutation in a gene that supervises the proper formation of collagen in the cell causes a lethal form of osteogenesis imperfecta, or brittle bone disease, when the infant inherits two faulty genes – one from each parent, according to researchers – including those from Baylor College of Medicine – in a report in the current issue of The New England Journal of Medicine.

BCM scientists, led by Dr. Brendan Lee, associate professor of molecular and human genetics and a Howard Hughes Medical Institute investigator, first identified the novel function in the gene CRTAP (cartilage-associate protein) and mutations in humans in a report in Cell in October. When CRTAP is mutated, the change prevents or reduces chemical modification of a particular protein called CASP that helps or "chaperones" collagen as it assumes its proper structure. Mice that lack CRTAP have severe osteoporosis and low bone mass. In mice, the disease can vary from mild to lethal. In the animal studies, the disease was inherited recessively – meaning that a mutated gene had to come from each parent.

However, in this study, scientists led by Dr. Joan Marini, chief of the bone and extracellular matrix branch at the National Institute of Child Health and Human Development, Lee from BCM, and several other U.S. research institutions analyzed the DNA of three infants born with osteogenesis imperfecta who died in the first year of life. All the babies had osteoporosis or brittle long bones and a narrow thorax with evidence of bone fractures that occurred before birth. When the DNA of the three children was studied, two had similar mutations in both CRTAP genes and the third had different mutations in each copy of the gene. They all lacked cartilage-associated protein, or CASP, which is critical for proper bone formation.

Previously identified forms of the disease were dominantly inherited. That means that a child had the disease if he or she inherited only one faulty gene. It was a random event unlikely to occur in subsequent or previous births to the family. However, doctors suspected a recessive form of the disease existed because some parents had more than one child with osteogenesis imperfecta.

"This report expands on the clinical phenotype (the discernable features that define the disease)," said Lee. "It describes the diagnostic parameters. It details what parts of different bones are affected and gives a clinical picture of the patients."

"At this point, we only see severe osteogenesis imperfecta when CRTAP is mutated," he said. "It raises the question about whether partial activity (of the gene or protein) could be found in milder forms of the disease."

While the more severe forms of osteogenesis imperfecta are fairly obvious, the milder forms of the disorder are sometimes confused with child abuse. Differentiating those with the disease from those who are being abused is important, said Lee, who is also director of the Skeletal Dysplasia Clinic at Texas Children's Hospital.

"This is still an open question that we are pursuing," he said.

Currently BCM offers the only test for this genetic defect and a related one that also results in osteogenesis imperfecta, he said.

Others who participated in the research include: Aileen M. Barnes, Weizhong Chang, Wayne A. Cabral, Thomas E. Uveges, Aarthi Ashok, Armando W. Flor, Elena Makareeva ,Natalia Kuznetsova, and Sergey Leikin from the NICHD; Roy Morello from BCM; MaryAnn Weis, and David R. Eyre from the University of Washington in Seattle, John J. Mulvihill, Patrick L. Wilson, from the University of Oklahoma Health Science Center in Oklahoma City and Usha T. Sundaram from the Medical College of Virginia.