Fibrodysplasia ossificans progressive was first documented in the 1600s, but it was not until the early twentieth century that anyone began to really study the disease (Martelli and Santos 2014). It wasn’t until very recently, about the last two decades, that we have made significant discoveries about this condition. FOP is one of the rarest diseases on the planet, so despite its devastating effects we have only just begun to discover how it works and how to potentially treat it (Martelli and Santos 2014).
A laboratory at the University of Pennsylvania headed by Dr. Frederick Kaplan is responsible for many of the key discoveries in FOPresearch (Kaplan et al 1998, 2013, 2016; Shafritz et al 1996; Feldman et al 2000; Gannon et al 2001; de la Peña et al 2005; Culbert et al 2014). The mutation that results in FOP was traced to a specific chromosome, and eventually the researchers were able to identify the mutation in the acvr1 gene that codes for the protein ACVR1, also known as ALK2. The affected protein is a BMP (bone morphogenetic protein) type I protein (Kaplan et al 2013). This pathway is involved with the differentiation of certain cell types into tissues such as bone (ten Dijke et al 2003).
If you look at the above image, you will see that there are both type I and type II receptors in this pathway. The type I receptor (ACVR1) forms a complex with the type II receptor (ten Dijke et al 2003). The BMP binds to the complex, and the type II BMP receptor activates the type I receptor via phosphorylation (ten Dijke et al 2003). The type I receptor is phosphorylated in its GS (glycine/serine) domain (ten Dijke et al 2003). That is important to note, because the FOP mutation occurs in that GS domain, also known as the activation or Smad-binding domain (Kaplan et al 2013). Once activated, the type I receptor proceeds to phosphorylate proteins known as (R)-Smads (ten Dijke et al 2003). The activation of specific Smad proteins leads to a signaling cascade that ultimately results in the binding of a Smad complex to DNA (ten Dijke et al 2003). The binding of the complex regulates the transcription of particular genes, which then eventually leads to cell differentiation and bone formation (ten Dijke et al 2003).