Searchable abstracts of presentations at key conferences on calcified tissues
Bone Abstracts (2019) 7 P121 | DOI: 10.1530/boneabs.7.P121

ICCBH2019 Poster Presentations (1) (226 abstracts)

An Acvr1[R258G] ‘conditional on' mouse model of atypical fibrodysplasia ossificans progressiva (FOP) is Activin A dependent

Lily Huang , Chris Schoenherr , Lili Wang , Xialing Wen , Joyce McClain , Qian Zhang , Kalyan Nannuru , Vincent Idone , Andrew Murphy , Aris Economides & Sarah Hatsell

Regeneron Pharmaceuticals, Tarrytown, USA.

FOP is an autosomal dominant disorder characterized by early onset, episodic and progressive ossification of skeletal muscle and associated connective tissue. FOP is driven by mutations in the intracellular domain of ACVR1 (ALK2), the most common of which is R206H. However, rare FOP causing mutations exist throughout the GS and the kinase domain of Acvr1. Several of these mutations result what appears to be a more severe FOP phenotype that includes significant developmental abnormalities in addition to the postnatal heterotopic bone formation. Two unrelated individuals with one such mutation, R258G, in the kinase domain of Acvr1 have a severe phenotype (Kaplan et al. 2015). We have modeled this mutation to investigate whether it results in a more severe phenotype in a mouse when present in the same genetic background as the more common R206H mutation. We engineered a Cre-regulated ‘conditional-ON’ allele of ACVR1[R258G] in the mouse, Acvr1[R258G]FlEx/+, similar to that previously used to model the R206H mutation (Hatsell, Idone et al. 2015). Body-wide activation of the FOP allele in Acvr1[R258G]FlEx/+;Gt(ROSA26)SorCreERt2/+ adult mice resulted in progressive ossification, evident radiographically as early as 2 weeks after dosing with tamoxifen in a similar manner to that seen with the previously published Acvr1R206HFlex mouse. Detailed studies to determine whether this mutation has a different and more severe embryonic phenotype compared to R206H are ongoing. We have previously shown that HO resulting from R206H mutation is Activin A dependent and can be completely blocked with the administration of an Activin A blocking antibody. Other FOP causing mutations also render Acvr1 responsive to Activin A (Hino et al 2015) suggesting Activin A blockade would also be effective in inhibiting HO formation induced by these mutations. Here we show that HO generated by the R258G mutation is also Activin A dependent in this mouse model.

Disclosure: All authors are are employees of Regeneron Pharmaceuticals Inc., and hold stock in the company.

Volume 7

9th International Conference on Children's Bone Health


Browse other volumes

Article tools

My recent searches

No recent searches.