Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements

Abstract

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.617G4A mutation, leading to the R206H substitution in the GS domain of the ACVR1 receptor. In two patients, we found a novel mutation c.774G4C, 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.

Peripheral Blood Mononuclear Cell Immunophenotyping in Fibrodysplasia Ossificans Progressiva Patients: Evidence for Monocyte DNAM1 Up‐regulation

“…Patients 1, 2, 3, 4, and 6 were previously described (8,25). Patient 5, never reported before, showed a classical FOP presentation with bilateral malformation of the great toes, cervical stiffness and first clinical manifestation at 6 years as ectopic ossification of a knee, first diagnosed as exostosis.…”

Classical and Atypical Fibrodysplasia Ossificans Progressiva in India

“…This allele has also been identified in several countries including South Africa, Korea, Spain, Italy, and Turkey (Bocciardi et al, 2009;Lee et al, 2009;Dandara et al, 2012;Morales-Piga et al, 2012;Eresen Yazıcıoglu et al, 2013). Our identification of the c.617G>A; p.Arg206His allele in 12 individuals, combined with the previous report of three Indian patients (Shukla et al, 2013), suggests that in India most cases of FOP result from this allelic variant.…”

“…Korea, France, Italy, Brazil, Spain, South, Africa, India, Mexico, Egypt, Turkish, China, Germany (Lin et al, 2006), (Nakajima et al, 2007), , (Lucotte et al, 2008), (Bocciardi et al, 2009), (Carvalho et al, 2010), (Morales-Piga et al, 2012), (Dandara et al, 2012), (Shukla et al, 2013), (Herrera-Esparza et al, 2013), (Al-Haggar et al, 2013), (Eresen Yazıcıoglu et al, 2013), (Zhang et al, 2013), (Stefanova et al, 2012) (Connor & Evans, 1982), (Stefanova et al, 2012), (Carvalho et al, 2010) Exons 8 and 9 c.1067 G>A p.Gly356Asp Present Japan, Germany, China (Kaplan et al, 2009), 3 (Furuya et al, 2008), (Stefanova et al, 2012), (Zhang et al, 2013) Exon 9 c.1124 G>C p.Arg375Pro Absent Unspecified (Kaplan et al, 2009) …”

Genetic abnormalities in Fibrodysplasia Ossificans Progressiva

“…Ratbi et al (2010) reported the case of a Moroccan patient with FOP carrying a rarely occurring mutation at c.774G>T of ACVR1 gene. Bocciardi et al (2009) reported the c.617G>A mutation, leading to the p.R206H substitution in the ACVR1 gene in 15 out of 17 Italian patients. In two patients, they found a novel mutation c.774G>C; p.R258S substitution (Bocciardi et al, 2009).…”

“…Bocciardi et al (2009) reported the c.617G>A mutation, leading to the p.R206H substitution in the ACVR1 gene in 15 out of 17 Italian patients. In two patients, they found a novel mutation c.774G>C; p.R258S substitution (Bocciardi et al, 2009). Furuya et al (2008) reported a 62-year-old man with slowly progressive FOP, and bearing a novel mutation in ACVR1.…”