Molecular Genetics of Fibrodysplasia Ossificans Progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is an autosomal‐dominant genetic disorder, caused by heterozygous mutations in the ACVR1 gene. Its defining clinical feature is heterotopic (extraskeletal) ossifications (HO). Almost all patients show also fibular deviation and shortness of the great toes from birth. However, the phenotypes of FOP patients vary and there seem to be a genotype–phenotype correlation even if the number of patients is still small to definitely establish it. Recent literature data support that all of the identified ACVR1 germ line missense mutations influence the postnatal induction of cartilage and bone cell differentiation. Moreover, it has been recently shown that the most common ACVR1 mutation p.R206H leads to a protein which causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, important discovery for new therapeutic approaches.

Key Concepts

  • FOP is caused by heterozygous missense activating mutations of the ACVR1 gene.
  • A clear genotype–phenotype correlation in FOP is highly presumable, even though the number of patients is small.
  • Analysis of the mutations, different from the common R206H mutation supply FOP research with valuable knowledge of the mechanisms of disease and possible therapeutic approaches.
  • Understanding of molecular mechanisms causing FOP is a major key step for developing therapy concepts.
  • Understanding FOP and the pathomechanisms of this extremely rare disease may be very helpful for the understanding of other more common forms of heterotopic ossifications, such as Posttraumatic Heterotopic Ossification and Neurogenic Heterotopic Ossification.

Keywords: FOP; ACVR1; heterotopic ossification; bone morphogenic protein type 1; genotype phenotype correlation

Figure 1. Schematic illustration of the ACVR1 protein and the mutations described up to date. ACVR1 consists of 509 amino acids and has four functional domains: a ligand‐binding domain, a transmembrane domain, a glycine–serine‐rich (GS‐rich) domain and a protein kinase domain. The ‘classical’ mutation p.R206H (dark blue) is located in the GS‐rich domain. The known mutations are located in either the GS‐rich domain or the protein kinase domain.
Figure 2. FOP (fibrodysplasia ossificans progressiva) mutations destabilise the inactive state. (a) FOP mutation sites are clustered around the regulatory GS domain and ATP (adenosine triphosphate) pocket. (b) αGS2 helix in ACVR1 is a hot spot for FOP mutations. Inset shows the likely charge repulsion between Q207E and FKBP12 Glu‐55. (c) Structural models show that FOP mutations break inhibitory interactions in the ACVR1‐FKBP12 structure. Changes in the mutant structure are coloured purple and overlaid onto the wild‐type residue coloured yellow. Hydrogen bonds in the wild type (yellow) and clashes in the mutant structure (purple) are shown by spheres and dashed lines, respectively. Models were generated using the Eris server. Reproduced from Chaikuad et al. 2012 under CC‐BY licence.
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Further Reading

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Rafati M, Mohamadhashem F, Hoseini A, Hoseininasab F and Ghaffari SR (2016) A novel ACVR1 mutation detected by whole exome sequencing in a family with an unusual skeletal dysplasia. European Journal of Medical Genetics 59: 330–336.

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Hüning, Irina, and Gillessen‐Kaesbach, Gabriele(Nov 2016) Molecular Genetics of Fibrodysplasia Ossificans Progressiva. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026930]