Fig. 1Schematic representation of the relationship between the activin A receptor, type I (ACVR1)/ALK2 gene, complementary DNA (cDNA) and protein. The ACVR1/ALK2 gene consist of 9 coding exons (Ex.) (black boxes). The ACVR1/ALK2 cDNA (1,530 bp) encodes a protein with 509 amino acids (a. a.). Mutations associated with fibrodysplasia ossificans progressiva are shown in the figure. The positions of the mutations in the cDNA and protein are indicated by numbers that begin from the adenine of the first ATG codon and Met residue, respectively. TGA, stop codon; SP, signal peptide; TM, transmembrane domain; GS, glycine/serine-rich domain; Ser/Thr kinase, serine/threonine kinase domain.
Fig. 2Schematic representation of signal transduction by ALK2 in response to ligand binding. ALK2 binds to a transforming growth factor-β family ligand, such as bone morphogenetic protein 6 (BMP6), BMP7, and BMP9, and acts as a type I receptor in co-operation with one of the type II receptors (BMP receptor type II [BMPR-II], activin receptor type IIA [ActR-IIA], and activin receptor type IIB [ActR-IIB]). Antagonists, such as follistatin, noggin, and chordin, directly bind to the ligand and prevent it from binding to receptors. Type II receptors are constitutively active kinases that phosphorylate the glycine/serine-rich domain (GS) domain of ALK2 to activate kinase activity. Activated ALK2 phosphorylates downstream substrates, such as Smad1, Smad5, and Smad8/9, and then binds to specific DNA sequences to regulate the transcription of its target genes. Ser/Thr, serine/threonine; P, phosphorylation; FKBP12, 12 kDa FK506-binding protein; Id1, inhibitor of DNA binding 1; BIT-1, BMP-inducible transcript-1.
Table 1Major Features of Patients with Fibrodysplasia Ossificans Progressiva
Malformation of the big toes at birth |
Swelling |
Heterotopic ossification in soft tissues (e.g., skeletal muscle, tendons, and ligaments) |
Disability progression: neck, spine, and shoulder > elbow, knee, hip, and jaw > wrist, ankle |
Autosomal dominant transmission |
Incidence: one patient per 2 million in the population |
Sporadic cases >> familial cases |
Table 2Inhibitors of ALK2 Signaling
Target |
Molecule |
Clinical trial |
Reference |
Ligand |
Anti-activin A antibody (REGN2477) |
Phase 2 |
[31] |
sActR-IIA-Fc |
[31] |
sActR-IIB-Fc |
[31] |
ALK2 kinase |
Dorsomorphin |
|
[39] |
LDN193189 |
[40] |
LDN212854 |
[42] |
K02288 |
[43] |
DMH-1 |
[41] |
ML347 |
[44] |
ALK2 mRNA |
Allele specific RNAi |
|
[4546] |
Exon skipping oligo DNA |
[47] |
Smads |
RARγ agonist (palovarotene) |
Phase 3 |
[4950] |
All-trans retinoic acid |
[48] |
BMP signaling |
Fendiline |
|
[54] |
Perhexiline |
[54] |
Differentiation |
Rapamycin |
Phase 2 |
[51] |
NG-391 |
[52] |
NG-393 |
[52] |
Trichocyalide A |
[53] |
Trichocyalide B |
[53] |