Fig. 1.
A genetically accurate and physiologically relevant mouse model of FOP. (A) Acvr1[R206H]FlEx (Acvr1tm2.1Vlcg; MGI:5763014) [1] is a conditional-on knock-in allele of ACVR1[R206H]. It was generated by introducing the R206H variant in exon 5 of mouse Acvr1, and then placing this mutant exon in the antisense orientation within intron 5 of Acvr1. In order to restore the function of Acvr1, a wild type exon 5 from human ACVR1 was placed upstream of the mutant exon (but in the sense strand), thereby preserving the structure of the resulting Acvr1 transcript. These elements – wild type exon 5 and mutant exon 5 – were flanked by FlEx arrays [29] in a manner such that upon action of Cre, the wild type exon is deleted and mutant exon 5 is placed into the sense strand. Thereby, Cre effectively converts the Acvr1[R206H]FlEx allele to Acvr1[R206H], and hence recreates – in mice – the genotype found in ACVR1R206H FOP patients. (B) HO (pseudocolored yellow) develops as early as 2 weeks post model initiation by tamoxifen administration in locations such as the back. This HO can expand over time and new lesions can form in close proximity, mirroring the expansions of the heterotopic bone field seen in human FOP. (C) In addition to the back, HO develops in other locations seen in FOP such as the limbs, sternum, ribcage, jaw, and hip. The location of each lesion is pinpointed by yellow arrows.