Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP)

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disorder of extensive and debilitating extra-skeletal bone formation. While the challenges of investigating a rare condition are many, the potential benefits are also great - not only for the specific disease under investigation, but also for the unique perspective on how cells normally function and the mechanisms that underlie more common disorders. This review will illustrate some of the many insights that we have gained by studying FOP.

Figure 1. The classic FOP phenotype

Classic fibrodysplasia ossificans progressiva (FOP) is defined by two characteristic clinical features. (a) Extensive heterotopic bone formation is seen in this 3-dimensional reconstructed computed tomography (CT) scan of the back of a twelve-year-old child. Flareups of FOP arise and progress in a well-defined spatial pattern that result in ribbons, sheets, and plates of bone that fuse the joints of the axial and appendicular skeleton, entombing the patient in a “second skeleton” of heterotopic bone. (b) An anteroposterior radiograph of the feet of a three-year-old child shows symmetrical great toe malformations of metatarsals and proximal phalanges along with microdactyly, fused interphalangeal joints, and hallux valgus deviations at the metatarsophalangeal joints.

Figure 2. ACVR1 mutation in classic FOP

A schematic of the ACVR1 protein is shown, with key functional domains indicated: the extracellular BMP ligand-binding domain, the single trans-membrane (TM) domain, the glycine-serine (GS) activation domain, and the protein kinase signaling domain. Amino acid positions of each domain boundary are indicated above the schematic. All patients who show the classic characteristic features of FOP have the identical mutation in codon 206 within the GS domain. The nucleotide and amino acid sequences of codons 204–208 are shown for the wild-type and FOP mutation. The classic FOP mutation (a G to A substitution at nucleotide position 617 of the cDNA) causes a substitution of histidine for arginine (Arg206His).

Figure 3. A hypothetical model for ligand-independent activation of BMP signaling in FOP

In the absence of BMP ligand, FKBP12 binds the wild-type type I BMP receptor (with arginine at codon 206; Arg206) and prevents “leaky” activation of downstream signaling in the absence of ligand. Upon BMP binding to the type I/type II BMP receptor complex, the type II receptor phosphorylates (asterisk) the type I receptor within the GS domain and induces the release of FKBP12 from the receptor and activation of downstream signaling. We hypothesize that FKBP12 does not correctly bind to the mutant FOP ACVR1 type I receptor (with histidine at codon 206; His206) either in the presence or the absence of BMP-receptor binding, allowing increased activation of BMP signaling.