Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
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 October 12, 2009
Citation Information: J Clin Invest. 2009;119(11):3462-3472. https://doi.org/10.1172/JCI37412.
View: Text | PDF
Research Article Bone Biology

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

  • Text
  • PDF
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

×

Figure 1

Mutant ACVR1 (c617A; R206H) activates the BMP signaling pathway.

Options: View larger image (or click on image) Download as PowerPoint
Mutant ACVR1 (c617A; R206H) activates the BMP signaling pathway.
(A) Act...
(A) Activation of ID1 transcription. COS-7 cells were cotransfected with an ID1 promoter luciferase reporter construct (–985/+94) and either human wild-type ACVR1 or mutant ACVR1 (R206H) expression vectors. Similar assays used U-2 OS and C2C12 cells. Data represent mean ± SEM (n > 3). (B) Induction of Smad1/5/8 phosphorylation. COS-7 (top) or MC3T3-E1 cells (bottom) were transfected with V5-tagged wild-type ACVR1 or c617A mutant ACVR1 (R206H) constructs or with the empty vector control (C). Immunoblot analysis for phosphorylated Smad1/5/8 showed induction of Smad1/5/8 phosphorylation without BMP treatment in cells expressing the mutant but not wild-type ACVR1 or empty vector constructs. Total Smad1 protein is shown. V5 antibody was used to detect the expression of the V5-tagged ACVR1 proteins. β-Actin was detected as a loading control. Data are representative of 3 individual experiments.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts