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Updated: Feb 19, 2026
Monitoring Leucine-Rich Repeat Containing 8 Channel (LRRC8/VRAC) Activity Using Sensitized-Emission Förster Resonance Energy Transfer (SE-FRET)
Published on: August 9, 2024
Variable signaling activity by FOP ACVR1 mutations
Julia Haupt1, Meiqi Xu1, Eileen M Shore2
1Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Research in FOP and Related Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract:
Most patients with fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder of heterotopic ossification, have the same causative mutation in ACVR1, R206H. However, additional mutations within the ACVR1 BMP type I receptor have been identified in a small number of FOP cases, often in patients with disease of lesser or greater severity than occurs with R206H mutations. Genotype-phenotype correlations have been suggested in patients, resulting in classification of FOP mutations based on location within different receptor domains and structural modeling. However while each of the mutations induces increased signaling through the BMP-pSmad1/5/8 pathway, the molecular mechanisms underlying functional differences of these FOP variant receptors remained undetermined. We now demonstrate that FOP mutations within the ACVR1 receptor kinase domain are more sensitive to low levels of BMP than mutations in the ACVR1 GS domain. Our data additionally confirm responsiveness of cells with FOP ACVR1 mutations to both BMP and Activin A ligands. We also have determined that constructs with FOP ACVR1 mutations that are engineered without the ligand-binding domain retain increased BMP-pSmad1/5/8 pathway activation relative to wild-type ACVR1, supporting that the mutant receptors can function through ligand-independent mechanisms either directly through mutant ACVR1 or through indirect mechanisms.
Insights
Fibrodysplasia ossificans progressiva (FOP) mutations in ACVR1 receptors show varied BMP signaling. Kinase domain mutations are more sensitive to BMP, and some variants activate pathways independently of ligand binding.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by heterotopic ossification.
- Most FOP cases are caused by the ACVR1 R206H mutation, but other ACVR1 mutations exist, correlating with varying disease severity.
- Previous studies suggested genotype-phenotype correlations, but the molecular mechanisms for functional differences in ACVR1 variant receptors remained unclear.
Purpose of the Study:
- To investigate the molecular mechanisms underlying functional differences among ACVR1 mutations in FOP.
- To determine the ligand sensitivity and signaling activation of different ACVR1 FOP mutant receptors.
- To explore potential ligand-independent activation mechanisms of mutant ACVR1 receptors.
Main Methods:
- Assessing BMP signaling pathway activation (pSmad1/5/8) in cells expressing different ACVR1 FOP mutant receptors.
- Comparing the sensitivity of kinase domain and GS domain ACVR1 mutations to varying BMP levels.
- Evaluating the response of mutant ACVR1 receptors to BMP and Activin A ligands.
- Analyzing ACVR1 constructs lacking the ligand-binding domain for ligand-independent signaling.
Main Results:
- ACVR1 mutations in the kinase domain exhibit higher sensitivity to low BMP concentrations compared to GS domain mutations.
- Cells with FOP ACVR1 mutations respond to both BMP and Activin A ligands.
- ACVR1 constructs with FOP mutations, even without the ligand-binding domain, show increased BMP-pSmad1/5/8 pathway activation compared to wild-type ACVR1.
- These findings suggest that mutant ACVR1 receptors can activate signaling pathways through ligand-independent mechanisms.
Conclusions:
- ACVR1 mutations in FOP exhibit distinct functional properties influencing BMP signaling pathway activation.
- The location of the mutation within the ACVR1 receptor impacts its sensitivity to BMP ligands.
- Ligand-independent activation mechanisms contribute to the aberrant signaling observed in FOP, offering potential therapeutic targets.
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