Dimori Milena, Toulany Mahtab, Sultana Lira Samia, Onal Melda, Thostenson Jeff D, Carroll John L, O'Brien Charles A, Morello Roy
Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
J Bone Miner Res. 2024 Dec 31;40(1):114-124. doi: 10.1093/jbmr/zjae189.
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 the primary vs 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.
成骨不全症（OI）是一类以遗传和临床异质性为特征的骨脆性疾病。几种不同的小鼠模型再现了OI的经典特征，最常研究的模型在Col1a1或Col1a2基因中携带自发或基因诱导的致病变异。当OI由I型胶原蛋白的原发性改变引起时，它代表一种全身性结缔组织疾病，除了骨骼外，还会影响多个骨骼外组织和器官，如皮肤、牙齿、肺、心脏等，这些组织和器官中也表达改变的I型胶原蛋白。目前，现有的小鼠模型在所有组织中都携带致病基因变异，无法评估突变对特定器官/系统的原发性和继发性后果。在此，我们描述了Col1a1的首个条件性敲入等位基因的产生，该等位基因可在α1(I)的三螺旋区域表达导致严重OI的甘氨酸替代（p.Gly1146Arg），但仅在选择的组织中经Cre驱动的重组后才会表达。我们将这个新的显性等位基因命名为Col1a1G1146R-Floxed/+，并将其引入小鼠模型。我们通过将携带该等位基因的小鼠与表达EIIA-Cre的小鼠杂交来描述其验证过程，并表明携带重组等位基因的后代再现了严重形式OI的经典特征。这个新的小鼠模型将有助于研究这种严重突变对肺、心脏等器官的组织特异性影响。
