The Fibrodysplasia Ossificans Progressiva (FOP) mutation p.R206H in ACVR1 confers an altered ligand response

Abstract

Patients with Fibrodysplasia Ossificans Progressiva (FOP) suffer from ectopic bone formation, which progresses during life and results in dramatic movement restrictions. Cause of the disease are point mutations in the Activin A receptor type 1 (ACVR1), with p.R206H being most common. In this study we compared the signalling responses of ACVR1 and ACVR1 to different ligands. ACVR1, but not ACVR1 inhibited BMP signalling of BMP2 or BMP4 in a ligand binding domain independent manner. Likewise, the basal BMP signalling activity of the receptor BMPR1A or BMPR1B was inhibited by ACVR1, but enhanced by ACVR1. In comparison, BMP6 or BMP7 activated ACVR1 and caused a hyper-activation of ACVR1. These effects were dependent on an intact ligand binding domain. Finally, the neofunction of Activin A in FOP was tested and found to depend on the ligand binding domain for activating ACVR1. We conclude that the FOP mutation ACVR1 is more sensitive to a number of natural ligands. The mutant receptor apparently lost some essential inhibitory interactions with its ligands and co-receptors, thereby conferring an enhanced ligand-dependent signalling and stimulating ectopic bone formation as observed in the patients.

BMP-7 induces apoptosis in human germinal center B cells and is influenced by TGF-β receptor type I ALK5

“…However, we were not able to show binding between BMP-7 and ALK5 (not shown), in line with previous data demonstrating that BMP-7 could bind to ALK2 and ALK3, but not to ALK5 [46, 47]. Based on this, we hypothesize that overexpression of truncated ALK5 in Mino cells might influence BMP-7-induced apoptosis indirectly by outcompeting other BMP type I receptors for complex formation with type II receptors, as has recently been demonstrated for ALK2 on BMP2/4-ALK3 mediated effects [48]. Still, in primary GC B cells, an ALK4/5/7 inhibitor counteracted BMP-7-induced apoptosis, further supporting a role of ALK5 as mediator for BMP-7 effects.…”

iPS cell technologies and their prospect for bone regeneration and disease modeling: A mini review

“…Researchers found that mineralization can be suppressed by a small molecule inhibitor of BMP signalling. In a subsequent study using a model of FOP derived from iPSCs-MSCs, the authors demonstrated that MMP1 and PAI1 have a pivotal effect on enhancing the chondrogenic features of FOP cells [47]. Recently, Barruet et al [48] used an FOP model derived from human iPSCs to investigate if mutation of ACVR1 R206H elevates the production of osteoprogenitors in the endothelial cell lineage.…”

Limb specific Acvr1‐knockout during embryogenesis in mice exhibits great toe malformation as seen in Fibrodysplasia Ossificans Progressiva (FOP)

“…For example, Chakkalakal et al developed chimeric Acvr1 knock‐in mice for FOP (Acvr1R206H/þ), which showed a malformation of the first digits in the hind limbs in radiographic analyses together with postnatal extra skeletal bone formation, recapitulating the human disease . Recently, it has been shown that the mutation p.R206H in ACVR1, with which the majority of FOP patients is diagnosed, leads to the loss of the inhibitory effect of ACVR1 on BMP signaling of BMP2 and BMP4 mediated by BMPR2 and BMPR1A or BMPR1B in vitro . Therefore, it is tempting to speculate that this inhibitory effect, which is no longer present, when ACVR1 is knocked out or carries a gain‐of‐function mutation, is crucial for the development of digit 1.…”

“…Ligands of the aforementioned receptors are predominantly BMPs, but can also be TGFβs and Activins (eg, Activin A) . In vitro studies showed that BMP2 and BMP4 prefer to form complexes with BMPR1A or BMPR1B and BMPR2, while BMP6 and BMP7 show their highest affinity to ACVR2A and ACVR2B in combination with ACVR1 . Activin A normally activates TGFβ signaling through its high affinity receptors ACVR2A and ACVR2B, in concert with ACVR1B and ACVR1C.…”

“…Until now, there is no causal therapy available, for which a therapeutic effect is clearly proven. Different studies showed that FOP‐associated mutations in Acvr1 lead to increased BMP signaling, including activation without exogenous stimulus as well as hyper‐activation in response to BMP ligands . In addition, in FOP, ACVR1 loses inhibitory functions and instead further promotes BMP signaling .…”