Fibrodysplasia ossificans progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP), a rare and disabling genetic condition of congenital skeletal malformations and progressive heterotopic ossification (HO), is the most catastrophic disorder of HO in humans. Episodic disease flare-ups are precipitated by soft tissue injury, and immobility is cumulative. Recently, a recurrent mutation in activin receptor IA/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, was reported in all sporadic and familial cases of classic FOP, making this one of the most highly specific disease-causing mutations in the human genome. The discovery of the FOP gene establishes a critical milestone in understanding FOP, reveals a highly conserved target for drug development in the transforming growth factor (TGF)-beta/BMP signalling pathway, and compels therapeutic approaches for the development of small molecule signal transduction inhibitors for ACVR1/ALK2. Present management involves early diagnosis, assiduous avoidance of iatrogenic harm, and symptomatic amelioration of painful flare-ups. Effective therapies for FOP, and possibly for other common conditions of HO, may potentially be based on future interventions that block ACVR1/ALK2 signalling.

Figure 1

Characteristic clinical features of fibrodysplasia ossificans progressive (FOP). (a) Extensive heterotopic bone formation typical of FOP is seen by three-dimensional reconstructed computed tomography scan of the back of a 12-year-old child. (b) Anteroposterior radiograph of the feet of a 3-year-old child shows symmetrical great toe malformations. Source: Shore et al. Nature Genet 2006; 38: 525–527. Copyright held by the authors.

Figure 2

Hypothetical schema of bone morphogenetic protein (BMP) signalling in fibrodysplasia ossificans progressiva (FOP) cells. In control cells (A), in the absence of ligand, the Smad/Smurf-FKBP12 (SM-FKBP12) complex binds activin receptor IA (ACVR1; a BMP type I receptor) and prevents its promiscuous phosphorylation by the constitutively active type II BMP receptor (not shown). SM-FKBP12 also promotes ubiquitin-associated degradation of ACVR1 in the absence of ligand, thus maintaining low steady-state levels of ACVR1 at the cell membrane. Following ligand binding in control cells (B), SM-FKBP12 dissociates from ACVR1, thus allowing the constitutively active BMP type II receptor (not shown) to phosphorylate ACVR1, and promote Smad 1, 5 and8 phosphorylation and downstream BMP signalling. In FOP cells, SM-FKBP12 does not appear to bind appropriately to the mutant receptor [ACVR1 (R206H)]. Thus, inhibition of BMP signalling is impaired in the absence of ligand, and basal leakiness of BMP signalling occurs (C). Additionally, it is suspected that since the SM-FKBP12 complex cannot properly target the mutant ACVR1 (R206H) receptor for ubiquitin-associated degradation, ACVR1 may be expected to accumulate at the cell surface. Thus, in the presence of ligand (D), hyper-responsive BMP signalling may be predicted to occur. Arrows, signalling promoted; blunt-end lines, signalling inhibited; lock, SM-FKBP12 binding to ACVR1; dashed lines, SM-FKBP12 binding to ACVR1 impaired; open cups, extracellular ligand-binding domain of ACVR1; filled-in circles, BMP ligand; filled-in circles inside open cups, BMP ligand binding to ACVR1.