A novel ACVR1 mutation in the glycine/serine-rich domain found in the most benign case of a fibrodysplasia ossificans progressiva variant reported to date

Abstract

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, autosomal dominant condition, classically characterised by heterotopic ossification beginning in childhood and congenital great toe malformations; occurring in response to a c.617 G > A ACVR1 mutation in the functionally important glycine/serine-rich domain of exon 6. Here we describe a novel c.587 T > C mutation in the glycine/serine-rich domain of ACVR1, associated with delayed onset of heterotopic ossification and an exceptionally mild clinical course. Absence of great toe malformations, the presence of early ossification of the cervical spine facets joints, plus mild bilateral camptodactyly of the 5th fingers, together with a novel ACVR1 mutation, are consistent with the 'FOP-variant' syndrome. The c.587 T > C mutation replaces a conserved leucine with proline at residue 196. Modelling of the mutant protein reveals a steric clash with the kinase domain that will weaken interactions with FKBP12 and induce exposure of the glycine/serine-rich repeat. The mutant receptor is predicted to be hypersensitive to ligand stimulation rather than being constitutively active, consistent with the mild clinical phenotype. This case extends our understanding of the 'FOP-variant' syndrome.

Fig. 1

Location of the novel L196P mutation. (A) Diagram illustrating the ACVR1 domain organisation with the L196P mutation shown in relation to the classical R206H FOP mutation. (B) Packing interactions of L196 in the wild-type ACVR1/FKBP12 structure. (C) The mutant L196 side chain would clash with I266 in the kinase domain (shown by a line of purple spheres). The GS and kinase domains are coloured orange and green, respectively. FKBP12 is coloured blue.

Fig. 2

Ossification within the soft tissues of the right thigh. The plain radiograph shows great strands and ribbons of ossification within the right thigh consistent with trauma from an intramuscular injection received 11 years earlier.

Fig. 3

Ossification within the right para-spinal muscles. Plain radiograph of the lumbar spine demonstrates extensive ossification within the right para-spinal muscles.

Fig. 4

Heterozygosity for the novel mutation c.587 T>C in ACVR1. Direct DNA sequencing electropherogram showing patient heterozygosity for the novel mutation c.587 T>C in exon 6 of the ACVR1 gene and the resultant substitution of leucine at residue 196 in unaffected control with proline in the patient.