ArticleBone2018
Variant BMP receptor mutations causing fibrodysplasia ossificans progressiva (FOP) in humans show BMP ligand-independent receptor activation in zebrafish.
Article in Bone, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 37 citations in OpenAlex.
- CryoEM structure of ALK2:BMP6 reveals distinct mechanism that allow ALK2 to interact with both BMP and activin ligands.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- Reduced GS Domain Serine/Threonine Requirements of Fibrodysplasia Ossificans Progressiva Mutant Type I BMP Receptor ACVR1 in the Zebrafish.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2023Article
- Novel Therapeutic Targets for Fibrodysplasia Ossificans Progressiva: Emerging Strategies and Future Directions.Cureus · 2023Review
- Functional comparison of human ACVR1 and zebrafish Acvr1l FOP-associated variants in embryonic zebrafish.Developmental dynamics : an official publication of the American Association of Anatomists · 2023Article
- Direct BMP signaling to chordoblasts is required for the initiation of segmented notochord sheath mineralization in zebrafish vertebral column development.Frontiers in endocrinology · 2023Article
- The Impact of Genetic Variability of TGF-Beta Signaling Biomarkers in Major Craniofacial Syndromes.Advances in experimental medicine and biology · 2023Review
- Functional Testing of Bone Morphogenetic Protein (BMP) Pathway Variants Identified on Whole-Exome Sequencing in a Patient with Delayed-Onset Fibrodysplasia Ossificans Progressiva (FOP) Using ACVR1Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2022Article
- Context-dependent tumor-suppressive BMP signaling in diffuse intrinsic pontine glioma regulates stemness through epigenetic regulation of CXXC5.Nature cancer · 2022Article
- Pathogenic ACVR1The EMBO journal · 2021Article
- BMP heterodimers signal via distinct type I receptor class functions.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Zebrafish Models for Human Skeletal Disorders.Frontiers in genetics · 2021Review
- Cercosporamide inhibits bone morphogenetic protein receptor type I kinase activity in zebrafish.Disease models & mechanisms · 2020Article
- Article
- Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas.Cancer cell · 2020Article
- Injury of Adult Zebrafish Expressing Acvr1lZebrafish · 2018Article
- Zebrafish Models of Rare Hereditary Pediatric Diseases.Diseases (Basel, Switzerland) · 2018Review
- The Horizon of a Therapy for Rare Genetic Diseases: A "Druggable" Future for Fibrodysplasia Ossificans Progressiva.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.