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The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization
Qi Shen, … , Mary C. Mullins, Eileen M. Shore
Qi Shen, … , Mary C. Mullins, Eileen M. Shore
Published November 2, 2009; First published October 12, 2009
Citation Information: J Clin Invest. 2009;119(11):3462-3472. https://doi.org/10.1172/JCI37412.
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Categories: Research Article Bone biology

The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization

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Abstract

Patients with classic fibrodysplasia ossificans progressiva, a disorder characterized by extensive extraskeletal endochondral bone formation, share a recurrent mutation (R206H) within the glycine/serine-rich domain of ACVR1/ALK2, a bone morphogenetic protein type I receptor. Through a series of in vitro assays using several mammalian cell lines and chick limb bud micromass cultures, we determined that mutant R206H ACVR1 activated BMP signaling in the absence of BMP ligand and mediated BMP-independent chondrogenesis that was enhanced by BMP. We further investigated the interaction of mutant R206H ACVR1 with FKBP1A, a glycine/serine domain–binding protein that prevents leaky BMP type I receptor activation in the absence of ligand. The mutant protein exhibited reduced binding to FKBP1A in COS-7 simian kidney cell line assays, suggesting that increased BMP pathway activity in COS-7 cells with R206H ACVR1 is due, at least in part, to decreased binding of this inhibitory factor. Consistent with these findings, in vivo analyses of zebrafish embryos showed BMP-independent hyperactivation of BMP signaling in response to the R206H mutant, resulting in increased embryonic ventralization. These data support the conclusion that the mutant R206H ACVR1 receptor in FOP patients is an activating mutation that induces BMP signaling in a BMP-independent and BMP-responsive manner to promote chondrogenesis, consistent with the ectopic endochondral bone formation in these patients.

Authors

Qi Shen, Shawn C. Little, Meiqi Xu, Julia Haupt, Cindy Ast, Takenobu Katagiri, Stefan Mundlos, Petra Seemann, Frederick S. Kaplan, Mary C. Mullins, Eileen M. Shore

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Figure 2

Reduced binding of FKBP12 to mutant ACVR1.

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Reduced binding of FKBP12 to mutant ACVR1.
COS-7 cells were cotransfecte...
COS-7 cells were cotransfected with FKBP1A expression vectors and wild-type ACVR1 or mutant ACVR1 (R206H) constructs. Following no treatment (–) or treatment (+) with 150 ng/ml BMP4, proteins were (A) immunoprecipitated with anti-FKBP1A/FKBP12 antibody, then immunoblotted with V5 antibody to detect V5-tagged ACVR1 or (B) immunoprecipitated with anti-ACVR1 antibody and immunoblotted to detect FKBP1A (top panels). The relative quantitative interactions between ACVR1 and FKBP12 are shown in the lower panels. Data represent mean ± SEM. *P < 0.05 versus wild-type without BMP treatment. The blots in lanes in A were run on the same gel but were noncontiguous (white line).
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