ArticleThe Journal of biological chemistry2010
Molecular consequences of the ACVR1(R206H) mutation of fibrodysplasia ossificans progressiva.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 112 citations in OpenAlex.
- Hepcidin as a Molecular Hub of Iron Homeostasis: From BMP-SMAD Signaling to Therapeutic Modulation.Biomolecules · 2026Review
- Single-base 2'OMe-modified LNA and MOE gapmers selectively silenceMolecular therapy. Nucleic acids · 2026Article
- Fibrodysplasia ossificans progressiva: genetic and clinical characterization in a cohort of Polish patients and review of potential therapies.Journal of applied genetics · 2026Review
- Advancements in mechanisms and drug treatments for fibrodysplasia ossificans progressiva.Journal of Zhejiang University. Science. B · 2025Review
- Role of the NF-kB signalling pathway in heterotopic ossification: biological and therapeutic significance.Cell communication and signaling : CCS · 2024Review
- FK506 bypasses the effect of erythroferrone in cancer cachexia skeletal muscle atrophy.Cell reports. Medicine · 2023Article
- Review
- Polypeptide Substrate Accessibility Hypothesis: Gain-of-Function R206H Mutation Allosterically Affects Activin Receptor-like Protein Kinase Activity.Biomolecules · 2023Article
- 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
- Suppression of heterotopic ossification in fibrodysplasia ossificans progressiva using AAV gene delivery.Nature communications · 2022Article
- Recent progress in drug development for fibrodysplasia ossificans progressiva.Molecular and cellular biochemistry · 2022Review
- Pathophysiology and Emerging Molecular Therapeutic Targets in Heterotopic Ossification.International journal of molecular sciences · 2022Review
- Protocol paper: a multi-center, double-blinded, randomized, 6-month, placebo-controlled study followed by 12-month open label extension to evaluate the safety and efficacy of Saracatinib in Fibrodysplasia Ossificans Progressiva (STOPFOP).BMC musculoskeletal disorders · 2022Article
- Monitoring and Management of Fibrodysplasia Ossificans Progressiva: Current Perspectives.Orthopedic research and reviews · 2022Review
- Pathogenic ACVR1The EMBO journal · 2021Article
- Activin-A Induces Early Differential Gene Expression Exclusively in Periodontal Ligament Fibroblasts fromBiomedicines · 2021Article
- Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva.Biomedicines · 2021Review
- Fibrodysplasia Ossificans Progressiva: What Have We Achieved and Where Are We Now? Follow-up to the 2015 Lorentz Workshop.Frontiers in endocrinology · 2021Review
- Review
- Insight into Molecular Mechanism for Activin A-Induced Bone Morphogenetic Protein Signaling.International journal of molecular sciences · 2020Article
9 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fibrodysplasia ossificans progressiva (FOP), a rare genetic and catastrophic disorder characterized by progressive heterotopic ossification, is caused by a point mutation, c.617G>A; p.R206H, in the activin A receptor type 1 (ACVR1) gene, one of the bone morphogenetic protein type I receptors (BMPR-Is). Although altered BMP signaling has been suggested to explain the pathogenesis, the molecular consequences of this mutation are still elusive. Here we studied the impact of ACVR1 R206H mutation on BMP signaling and its downstream signaling cascades in murine myogenic C2C12 cells and HEK 293 cells. We found that ACVR1 was the most abundant of the BMPR-Is expressed in mesenchymal cells but its contribution to osteogenic BMP signal transduction was minor. The R206H mutant caused weak activation of the BMP signaling pathway, unlike the Q207D mutant, a strong and constitutively active form. The R206H mutant showed a decreased binding affinity for FKBP1A/FKBP12, a known safeguard molecule against the leakage of transforming growth factor (TGF)-beta or BMP signaling. The decreased binding affinity of FKBP1A to the mutant R206H ACVR1 resulted in leaky activation of the BMP signal, and moreover, it decreased steady-state R206H ACVR1 protein levels. Interestingly, while WT ACVR1 and FKBP1A were broadly distributed in plasma membrane and cytoplasm without BMP-2 stimulation and then localized in plasma membrane on BMP-2 stimulation, R206H ACVR1 and FKBP1A were mainly distributed in plasma membrane regardless of BMP-2 stimulation. The impaired binding to FKBP1A and an altered subcellular distribution by R206H ACVR1 mutation may result in mild activation of osteogenic BMP-signaling in extraskeletal sites such as muscle, which eventually lead to delayed and progressive ectopic bone formation in FOP patients.
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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.