Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1

Abstract

Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant human disorder of bone formation that causes developmental skeletal defects and extensive debilitating bone formation within soft connective tissues (heterotopic ossification) during childhood. All patients with classic clinical features of FOP (great toe malformations and progressive heterotopic ossification) have previously been found to carry the same heterozygous mutation (c.617G>A; p.R206H) in the GS activation domain of activin A type I receptor/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor. Among patients with FOP-like heterotopic NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript ossification and/or toe malformations, we identified patients with clinical features unusual for FOP. These atypical FOP patients form two classes: FOP-plus (classic defining features of FOP plus one or more atypical features) and FOP variants (major variations in one or both of the two classic defining features of FOP). All patients examined have heterozygous ACVR1 missense mutations in conserved amino acids. While the recurrent c.617G>A; p.R206H mutation was found in all cases of classic FOP and most cases of FOP-plus, novel ACVR1 mutations occur in the FOP variants and two cases of FOP-plus. Protein structure homology modeling predicts that each of the amino acid substitutions activates the ACVR1 protein to enhance receptor signaling. We observed genotype-phenotype correlation between some ACVR1 mutations and the age of onset of heterotopic ossification or on embryonic skeletal development.

Signaling Receptors for TGF-β Family Members

“…FOP is caused by activating mutation in the sequence of the ACVR1/ALK2 gene that encodes the GS domain of ActRI/ALK-2 (Shore et al 2006;Kaplan et al 2009). The mutated receptor requires the presence of a type II receptor, either the BMP type II receptor or ActRII, for full activity; the kinase activity of the type II receptor is not needed suggesting that it acts as a scaffolding molecule (Bagarova et al 2013).…”

Osteogenic Gene Expression Correlates With Development of Heterotopic Ossification in War Wounds

“…Familial forms of the condition include progressive osseous heteroplasia and Albright hereditary osteodystrophy [48]. Recurrent mutations in the BMP type-1 receptor, activin receptor IA (ACVR1), and local changes in the expression of BMP-4 and its receptor (BMPR1A) have been linked to the rare genetic disorder fibrodysplasia ossificans progressiva [11,13,18,20,26]. The more common acquired forms of HO frequently occur as a complication of THA, elbow or acetabular fractures requiring surgical treatment, soft tissue injury secondary to trauma or deep muscle dissection, and traumatic brain or spinal cord injuries [3,7,8,25,49].…”

Neofunction of ACVR1 in fibrodysplasia ossificans progressiva

“…The responsive mutation for classic FOP is 617G > A (R206H) in the intracellular glycineand serine-rich (GS) domain (7) of ACVR1 (also known as ALK2), a type I receptor for bone morphogenetic protein (BMP) (8)(9)(10). ACVR1 mutations in atypical FOP patients have been found also in other amino acids of the GS domain or protein kinase domain (11,12). Regardless of the mutation site, mutated ACVR1 (FOP-ACVR1) has been shown to activate BMP signaling without exogenous BMP ligands (constitutive activity) and transmit much stronger BMP signaling after ligand stimulation (hyperactivity) (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”