ZFIN ID: ZDB-PUB-180109-3
Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish
Mucha, B.E., Hashiguchi, M., Zinski, J., Shore, E.M., Mullins, M.C.
Date: 2018
Source: Bone   109: 225-231 (Journal)
Registered Authors: Mullins, Mary C.
Keywords: ACVR1, BMP signaling, Dorsal-ventral embryonic patterning, FOP, Smad1/5, Zebrafish
MeSH Terms:
  • Activin Receptors, Type I/genetics
  • Activin Receptors, Type I/metabolism
  • Animals
  • Bone Morphogenetic Protein Receptors/genetics
  • Bone Morphogenetic Protein Receptors/metabolism*
  • Humans
  • Mutation
  • Myositis Ossificans/genetics
  • Myositis Ossificans/metabolism*
  • Protein Binding/genetics
  • Protein Binding/physiology
  • Signal Transduction/genetics
  • Signal Transduction/physiology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
PubMed: 29307777 Full text @ Bone
The large majority of cases of the autosomal dominant human disease fibrodysplasia ossificans progressiva (FOP) are caused by gain-of-function Arg206His mutations in the BMP type I receptor ACVR1 (ALK2). The Arg206His mutation is located in the GS domain of the type I receptor. This region is normally phosphorylated by the BMP type II receptor, which activates the type I receptor to phosphorylate its substrate, the signal transducer Smad1/5/8. A small subset of patients with FOP carry variant mutations in ACVR1 altering Gly328 to Trp, Glu or Arg. Since these mutations lie outside the GS domain, the mechanism through which ACVR1 Gly328 mutations cause disease remains unclear. We used a zebrafish embryonic development assay to test the signaling of human ACVR1 Gly328 mutant receptors comparing them to the Arg206His mutant. In this assay increased or decreased BMP pathway activation alters dorsal-ventral axial patterning, providing a sensitive assay for altered BMP signaling levels. We expressed the human ACVR1 Gly328 mutant receptors in zebrafish embryos to investigate their signaling activities. We found that all ACVR1 Gly328 human mutations ventralized wild-type embryos and could partially rescue Bmp7-deficient embryos, indicating that these mutant receptors can activate BMP signaling in a BMP ligand-independent manner. The degree of ventralization or rescue was similar among all three Gly328 mutants. Smad1/5 phosphorylation, a readout of BMP receptor signaling, was mildly increased by ACVR1 Gly328 mutations. Gene expression analyses demonstrate expanded ventral and reciprocal loss of dorsal cell fate markers. This study demonstrates that Gly328 mutants increase receptor activation and BMP ligand-independent signaling through Smad phosphorylation.