PHENOTYPIC VARIABILITY AND INCOMPLETE PENETRANCE OF SPONTANEOUS FRACTURES IN AN INBRED STRAIN OF TRANSGENIC MICE EXPRESSING A MUTATED COLLAGEN GENE (COL1A1)

Phenotype variability and incomplete penetrance are frequently observe d in human monogenic diseases such as osteogenesis imperfecta. Here an inbred strain of transgenic mice expressing an internally deleted gen e for the pro alpha 1(I) chain of type I procollagen (COL1A1) was bred to mild type mice of the same strain so that the inheritance of a fra cture phenotype could be examined in a homogeneous genetic background. To minimize the effects of environmental factors, the phenotype was e valuated in embryos that were removed from impregnated females 1 d bef ore term. Examination of stained skeletons from 51 transgenic embryos from 11 separate litters demonstrated that similar to 22% had a severe phenotype with extensive fractures of both long bones and ribs, simil ar to 51% had a mild phenotype with fractures of ribs only, and simila r to 27% had no fractures. The ratio of steady-state levels of the mRN A from the transgene to the level of mRNA from the endogenous gene was the same in all transgenic embryos. The results demonstrated that the phenotypic variability and incomplete penetrance were not explained b y variations in genetic background or levels in gene expression. Inste ad, they suggested that phenotypic variation is an inherent feature of expression of a mutated collagen gene.