A new Col1a1 conditional knock-in mouse model to study osteogenesis imperfecta

Abstract Osteogenesis imperfecta (OI) constitutes a family of bone fragility disorders characterized by both genetic and clinical heterogeneity. Several different mouse models reproduce the classic features of OI, and the most-commonly studied carry either a spontaneous or genetically induced pathogenic variant in the Col1a1 or Col1a2 gene. When OI is caused by primary alterations of type I collagen, it represents a systemic connective tissue disease that, in addition to the skeleton, also affects several extra-skeletal tissues and organs such as skin, teeth, lung, heart, and others, where the altered type I collagen is also expressed. Currently, existing mouse models harbor a disease-causing genetic variant in all tissues and do not allow assessing primary versus secondary consequences of the mutation on a specific organ/system. Here, we describe the generation of the first conditional knock-in allele for Col1a1 that can express a severe OI-causing glycine substitution (p.Gly1146Arg) in the triple helical region of α1(I) but only after Cre-driven recombination in the tissue of choice. We called this new dominant allele Col1a1G1146R-Floxed/+ and introduced it into the murine model. We describe its validation by crossing mice carrying this allele with EIIA-Cre expressing mice and showing that offspring with the recombined allele reproduce the classic features of a severe form of OI. The new mouse model will be useful to study the tissue-specific impact of this severe mutation on organs such as the lung, the heart and others.