Transgenic mice that express a mini-gene version of the human gene for type I procollagen (COL1A1) develop a phenotype resembling a lethal form of osteogenesis imperfecta.

A mini-gene version of the human gene for a pro-alpha 1(I) chain of type I procollagen (COL1A1) was prepared that contained -2.5 kilobases of the promoter region and the 5'- and 3'-ends of the gene but lacked a large central region containing 41 exons. The construct was modeled after a sporadic in-frame deletion of the human gene that produced a lethal variant of osteogenesis imperfecta, because it caused synthesis of shortened pro-alpha 1(I) chains that associated with normal pro-alpha 1(I) and pro-alpha 2(I) chains and caused degradation of both the shortened and normal pro-alpha chains through a process called procollagen suicide. The mini-gene was used to prepare transgenic mice. Eight of 15 transgenic mice expressed varying levels of the gene. All except one of the Fo founders were phenotypically normal, but several of the founders were apparently mosaic since they produced F1 progeny that died shortly after birth with a distinctive phenotype. The phenotype included extensive fractures of ribs and long bones similar to the fractures seen in lethal variants of osteogenesis imperfecta. Mice with the lethal phenotype expressed much higher levels of the mini-gene than transgenic mice without the lethal phenotype. Experiments with cultured skin fibroblasts from the transgenic mice demonstrated that shortened pro-alpha 1(I) chains synthesized from the mini-gene became disulfide-linked to pro-alpha 1(I) chains synthesized from the endogenous mouse gene. The results demonstrate that a mutated type I procollagen gene based on the model of procollagen suicide can be used to produce a severe phenotype of osteogenesis imperfecta that is genetically transmitted.