Study provides new explanation for 'brittle bone,' connective tissue disease

By Ruth SoRelle, M.P.H.

Mutations in a previously unstudied gene key to the proper formation of the structure of collagen can cause osteogenesis imperfecta, or brittle bone disease, in both mice and man, said researchers from Baylor College of Medicine and a group of international collaborators in a report that appears in a recent issue of the journal Cell.

Changes in genes that serve the same purpose for different forms of collagen may also be at the root of other connective tissue diseases, said the report's senior author, Brendan Lee, M.D., Ph.D., associate professor of molecular and human genetics at BCM, director of the Skeletal Dysplasia Clinic at Texas Children's Hospital and a Howard Hughes Medical Institute investigator.

"This is truly a novel molecular or biochemical mechanism that causes human connective tissue disease," said Lee.

Mutations in CRTAP (cartilage-associated protein) reduce or prevent chemical modification of a particular protein that helps to chaperone collagen as it assumes its proper structure. That particular modification, which involves attaching a hydroxy (OH) molecule onto the protein, is a process called prolyl 3-hydroxylation.

Mutation targets protein

Mice bred to lack CRTAP have severe osteoporosis and low bone mass – the mouse equivalent of osteogenesis imperfecta. What makes this finding interesting, said Lee, is that it can cause a whole spectrum of brittle bone disease in humans from lethal to mild forms, depending on the effect of the mutation. When the mutation eliminates the protein associated with the gene, a severe, lethal form of osteogenesis imperfecta results. Other mutations can result in less of the protein and are associated with a milder form of the disease.

More broadly, this finding lends itself to the hypothesis that mutations in similar genes might cause problems resulting in diseases related to defects in other types of collagen. Collagen is the most common protein in the human body, and the four most common types are found in different types of tissues including bone, cartilage, blood vessels, and kidney.

"A logical extension of this research might be that we would find mutations in related genes affecting these other types of connective tissues," Lee said.

New inheritance pattern

More specifically, the finding explains a mystery surrounding osteogenesis imperfecta. Previously, the only gene mutation known to cause the disease was dominantly inherited. That means if a person has the mutated gene, he or she has the disease. This means that the mutation causing the disease in the first person in a family is spontaneous and not inherited from a parent.

However, in some families, more than one child has the disease, indicating it is inherited. This new mechanism for the disease is genetically recessive, with each parent having one mutated gene and one normal gene. They then have a one in four chance of having a child with osteogenesis imperfect with each pregnancy.

"This proves a new inheritance pattern for OI and a new mechanism for bone disease," said Lee.

More research on connective tissue diseases

Current studies are aimed at answering whether this problem with prolyl-3-hydroxylation is involved in other connective tissue diseases.

Others who participated in the research include: Drs. Roy Morello, Terry Bertin, Yuqing Chen and John Hicks of Baylor College of Medicine; Laura Tonachini, Massimiliano Monticone and Patrizio Castagnola of the Istituto Nazionale per la Ricerca sul Cancro in Genova, Italy; Frank Rauch and Francis H. Glorieux of Shriners Hospital for Children and McGill University, Montreal, Canada; Janice Vranka and Hans of Peter Bachinger of Shriners Hospital for Children in Portland, Oregon, and the Oregon Health & Science University; James M. Pace, Ulrike Schwarze, Peter H. Byers, MaryAnn Weis and Russell J. Femandes of the University of Washington in Seattle; and David R. Eyre, Zhenqiang Yao and Brendan F. Boyce of the University of Rochester Medical Center in New York.

Funding for the research came from the National Institutes of Health, the Baylor College of Medicine Mental Retardation Developmental Disabilities Research Center and the Shriners of North America.