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GENATLAS PHENOTYPE
last update : 03-04-2018
Symbol FOP
Location 2q24.1
Name fibrodysplasia ossificans progressiva
Corresponding gene ACVR1
Main clinical features
  • presence of malformations of the great toes with hallux valgus and post-natal progressive heterotopic ossification that results in the formation of the ectopic skeleton
  • characterized by postnatal progressive heterotopic ossification of muscle, tendon, ligament and fascia, and by congenital malformation of the great toes with a fatal outcome resulting, most often, from complications of severe restrictive-chest-wall disease
    • Genetic determination autosomal dominant
    Function/system disorder osteo-articular
    Type disease
    Gene product
    Name ALK2, activin A receptor, type II-like kinase 2
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    missense   abnormal protein/gain of function R206H, forming a shorter side chain that alters the electrostatic potential and interactions with the GS activation domain, predicting destabilization of the GS domain, consistent with constitutive activation, perturbing BMP signaling
    Remark(s) .altered BMP receptor trafficking may play a significant role in FOP pathogenesis
  • ALK2 (R206H) is a constitutively activated BMP receptor and cooperatively induces osteoblastic differentiation with SMAD1 and SMAD5, which are increased during muscle regeneration (Fukuda 2008)
  • ALK2(G356D) inhibits myogenesis and induces osteoblastic differentiation
  • dorsomorphin and its derivatives may be useful for treating FOP caused by not only ALK2(R206H) but also ALK2(G356D) (Fukuda 2008)
  • dysregulated ALK2 kinase activity involved in the pathogenesis of FOP
  • heterotopic bone formation in FOP may be induced by a constitutively activated BMP receptor signaling through Smad1 or Smad5 (Fukuda 2009)
  • ALK2(L196P), the most benign FOP variant case, is an activated BMP receptor equivalent to ALK2(R206H) and ALK2(L196P) activity may be suppressed by a novel molecular mechanism in patients with this mutation (PMID: 21377447))
  • FOP-associated mutations in ALK2 reduce binding of the inhibitor FKBP12 and promote leaky signaling in the absence of ligand (PMID: 22977237))
  • at least one effect of ALK2 gain-of-function mutations in FOP patients is enhanced chondrogenic differentiation which supports formation of heterotopic endochondral bone (PMID: 24449086))
  • ACVR1(R206H) causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, demonstrating that this ligand is necessary and sufficient for driving heterotopic ossification (HO) in a genetically accurate model of FOP (PMID: 26333933))
    • Genotype/Phenotype correlations mutation G356D in the kinase domain associated to slow progressive FOP (Fukuda 2008)