Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare genetic 
disorder characterized by congenital great toe malformations and progressive 
heterotopic ossification transforming skeletal muscles and connective tissues to 
bone following a well-defined anatomic pattern of progression. Recently, FOP has 
been associated with a specific mutation of ACVR1, the gene coding for a bone 
morphogenetic protein type I receptor. The identification of ACVR1 as the 
causative gene for FOP now allows the genetic screening of FOP patients to 
identify the frequency of the identified recurrent ACVR1 mutation and to 
investigate genetic variability that may be associated with this severely 
debilitating disease. We report the screening for mutations in the ACVR1 gene 
carried out in a cohort of 17 Italian patients. Fifteen of these displayed the 
previously described c.617G>A mutation, leading to the R206H substitution in the 
GS domain of the ACVR1 receptor. In two patients, we found a novel mutation 
c.774G>C, leading to the R258S substitution in the kinase domain of the ACVR1 
receptor. In the three-dimensional model of protein structure, R258 maps in 
close proximity to the GS domain, a key regulator of ACVR1 activity, where R206 
is located. The GS domain is known to bind the regulatory protein FKBP12 and to 
undergo multiple phosphorylation events that trigger a signaling cascade inside 
the cell. The novel amino-acid substitution is predicted to influence either the 
conformation/stability of the GS region or the binding affinity with FKBP12, 
resulting in a less stringent inhibitory control on the ACVR1 kinase activity.