Molecular Genetics of Fibrodysplasia Ossificans Progressiva

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Abstract Fibrodysplasia ossificans progressiva (FOP, MIM# 135100) is an autosomal‐dominant genetic disorder, caused by heterozygous mutations in the ACVR1 gene. While most with FOP have the same single‐nucleotide substitution (c.617G>A; R206H), occasional variant mutations in ACVR1 have also been identified. The defining clinical features of FOP are malformations of the great toes and progressive heterotopic (extraskeletal) ossification (HO). However, the clinical presentations among FOP patients vary and, at least in some cases, there appear to be genotype–phenotype correlations with specific ACVR1 mutations, even among the small number of patients. FOP‐associated ACVR1 mutations are activating mutations that enhance signalling through the BMP‐pSmad1/5 signalling pathway and direct the induction of cartilage and bone cell differentiation to form ectopic bone in postnatal soft connective tissues. Recent studies examining the molecular mechanisms, reveal that the mutant ACVR1 receptors have lost the normal constraints that regulate the activation of the ACVR1 receptor signalling complex. Key Concepts Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of heterotopic ossification. FOP is caused by heterozygous activating mutations in the ACVR1 gene. Most FOP patients share the identical ACVR1 c.617G>A mutation that causes a single amino acid substitution (R206H). Additional variant mutations have been identified in ACVR1 and are associated with distinct clinical manifestations in some cases. ACVR1 is a type I receptor in the BMP signalling pathway, an important pathway in regulating bone formation. FOP mutant ACVR1 receptors have lost regulatory constraints that control how downstream signalling is activated.