ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP‐induced osteoblast differentiation and bone formation

  title={ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP‐induced osteoblast differentiation and bone formation},
  author={Maarten van Dinther and Nils Visser and David J J de Gorter and Joyce Doorn and Marie Jos{\'e} Goumans and Jan de Boer and Peter ten Dijke},
  journal={Journal of Bone and Mineral Research},
Fibrodysplasia ossificans progressiva (FOP) is a rare disabling disease characterized by heterotopic ossification for which there is currently no treatment available. [] Key Result Expression of the mutant ALK2-R206H receptor (FOP-ALK2) results in increased phosphorylation of the downstream Smad1 effector proteins and elevated basal BMP-dependent transcriptional reporter activity, indicating that FOP-ALK2 is constitutively active.
Hyperactive BMP signaling induced by ALK2R206H requires type II receptor function in a Drosophila model for classic fibrodysplasia ossificans progressiva
  • Viet Q Le, K. Wharton
  • Biology, Medicine
    Developmental dynamics : an official publication of the American Association of Anatomists
  • 2012
These studies provide a compelling example for Drosophila as a model organism to study the molecular underpinnings of complex human syndromes such as FOP, as the normal interplay between such disparate behaviors could be shifted by the presence of ALK2R206H receptors.
Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish
Results demonstrate that FOP-ACVR1 is not constrained by the same receptor/ligand partner requirements as WT- ACVR1, and has the ability to respond to both Bmp7 and Activin A ligands.
Development of Macrocycle Kinase Inhibitors for ALK2 Using Fibrodysplasia Ossificans Progressiva‐Derived Endothelial Cells
Fibrodysplasia ossificans progressiva (FOP) is an extremely rare congenital form of heterotopic ossification (HO), caused by heterozygous mutations in the activin A type I receptor (ACVR1), that
Alk2 Regulates Early Chondrogenic Fate in Fibrodysplasia Ossificans Progressiva Heterotopic Endochondral Ossification
Analysis of murine mesenchymal progenitor cells establishes ALK2 as a plausible therapeutic target during early chondrogenic stages of lesion formation for preventing heterotopic bone formation in FOP and other conditions.
Antisense-Oligonucleotide Mediated Exon Skipping in Activin-Receptor-Like Kinase 2: Inhibiting the Receptor That Is Overactive in Fibrodysplasia Ossificans Progressiva
The designs designed in this study provide a potential therapeutic approach for the treatment of FOP disease by reducing the excessive ALK2 activity in FOP patients by means of exon skipping.
Molecular Consequences of the ACVR1R206H Mutation of Fibrodysplasia Ossificans Progressiva*
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.
Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva
The molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation are described and existing therapeutic alternatives are summarized and focus on repositioned drugs in FOP, at preclinical and clinical stages.
Structure of the Bone Morphogenetic Protein Receptor ALK2 and Implications for Fibrodysplasia Ossificans Progressiva*
The presented ALK2 structure offers a valuable template for the further design of specific inhibitors of BMP signaling, and FOP mutations break critical interactions that stabilize the inactive state of the kinase, thereby facilitating structural rearrangements that diminish FKBP12 binding and promote the correct positioning of the glycine-serine-rich loop and αC helix for kinase activation.


A unique mutation of ALK2, G356D, found in a patient with fibrodysplasia ossificans progressiva is a moderately activated BMP type I receptor.
Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP)
The recurrent single nucleotide missense mutation in the gene encoding activin receptor IA/activin-like kinase-2 (ACVR1/ALK2), a bone morphogenetic protein type I receptor that causes skeletal metamorphosis in all classically affected individuals worldwide, is the first identified human metamorphogene.
Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism.
The first known small-molecule inhibitor of BMP signaling-dorsomorphin is described, which was identified in a screen for compounds that perturb dorsoventral axis formation in zebrafish and found that dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6 and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation.
Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva.
Overexpression of a potent bone-inducing morphogen (bone morphogenetic protein 4) in lymphocytes is associated with the disabling ectopic osteogenesis of fibrodysplasia ossificans progressiva.
Bone Morphogenetic Protein-9 Is a Circulating Vascular Quiescence Factor
BMP9, circulating under a biologically active form, is a potent antiangiogenic factor that is likely to play a physiological role in the control of adult blood vessel quiescence.
BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis
It is demonstrated that ALK1 is a signalling receptor for bone morphogenetic protein-9 (BMP-9) in endothelial cells (ECs) and found to inhibit basic fibroblast growth factor-stimulated proliferation and migration of bovine aortic ECs and to block vascular endothelial growth factor (VEGF)-induced angiogenesis.
Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4.
Results suggest thatALK-3 and ALK-6 are type I receptors for OP-1 and BMP-4; in addition, ALk-2 is a type I receptor shared by activin and OP- 1, but not by B MP-4.
Identification and Functional Characterization of Distinct Critically Important Bone Morphogenetic Protein-specific Response Elements in the Id1 Promoter*
It is reported that Id1, a dominant negative inhibitor of basic helix-loop-helix proteins, is a direct target gene for BMP, and the results provide important new insights into how the BMP/Smad pathway can specifically activate target genes.
Functional Modeling of the ACVR1 (R206H) Mutation in FOP
Protein modeling predicts that substitution with histidine creates a pH-sensitive switch within the activation domain of the receptor that leads to ligand-independent activation of ACVR1 in fibrodysplasia ossificans progressiva.