PUBLICATION

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

Authors
Shen, Q., Little, S.C., Xu, M., Haupt, J., Ast, C., Katagiri, T., Mundlos, S., Seemann, P., Kaplan, F.S., Mullins, M.C., and Shore, E.M.
ID
ZDB-PUB-091101-15
Date
2009
Source
J. Clin. Invest.   119(11): 3462-3472 (Journal)
Registered Authors
Little, Shawn, Mullins, Mary C.
Keywords
none
MeSH Terms
  • COS Cells
  • Zebrafish/embryology*
  • Myositis Ossificans/genetics*
  • Chondrogenesis/genetics
  • Chondrogenesis/physiology*
  • Chick Embryo
  • Mutation/genetics*
  • Chlorocebus aethiops
  • Body Patterning
  • Protein Binding
  • Bone Morphogenetic Proteins/metabolism*
  • Signal Transduction/genetics*
  • Animals
  • Activin Receptors, Type I/genetics*
  • Cell Line
  • Smad Proteins, Receptor-Regulated/metabolism
(all 16)
PubMed
19855136 Full text @ J. Clin. Invest.
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.
Genes / Markers
Figures
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Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
WT + MO4-smad5 + MO5-smad5standard conditions1-4 somites
WT + MO4-smad5 + MO5-smad5standard conditions1-4 somites
acvr1ltm110b/tm110bstandard conditionsPrim-5
acvr1ltm110b/tm110bstandard conditionsPrim-5
acvr1ltm110b/tm110bstandard conditionsPrim-5
1 - 5 of 5
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
sb1aub
    		Point Mutation
    tdc24
      		Point Mutation
      tm110b
        		Point Mutation
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        Fish
        Antibodies
        Orthology
        Engineered Foreign Genes
        No data available
        Mapping
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        Citation
        Shen, Q., Little, S.C., Xu, M., Haupt, J., Ast, C., Katagiri, T., Mundlos, S., Seemann, P., Kaplan, F.S., Mullins, M.C., and Shore, E.M. (2009) The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J. Clin. Invest.. 119(11):3462-3472.