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Twists in the fibrodysplasia ossificans progressiva story challenge and expand our understanding of BMP biology.

ABSTRACT: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare, debilitating disease in which heterotopic bone is formed in certain soft tissues. A gain-of-function variant in the cytoplasmic domain of the activin A receptor type I (ACVR1) exists in all patients with FOP. Strikingly, these FOP-causing variants imbue a neofunction to ACVR1 - the ability to recognize activin A as an agonist with bone morphogenic protein-like signaling that leads to heterotopic ossification (HO). These findings are supported by the efficacy of anti-activin A antibodies in preventing HO in FOP mice. This surprising story continues in companion papers in this issue of the JCI. Aykul et al. and Lees-Shepard et al. independently found that antibodies against ACVR1, which were being developed as potential therapeutics for FOP, instead caused HO in FOP mice. While this unexpected finding may be the clinical final act for such antibodies, it provides another twist in the unique and evolving FOP story.

SUBMITTER: Collins MT

PROVIDER: S-EPMC9197510 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Twists in the fibrodysplasia ossificans progressiva story challenge and expand our understanding of BMP biology.

Collins Michael T MT

The Journal of clinical investigation 20220601 12

Fibrodysplasia ossificans progressiva (FOP) is an ultrarare, debilitating disease in which heterotopic bone is formed in certain soft tissues. A gain-of-function variant in the cytoplasmic domain of the activin A receptor type I (ACVR1) exists in all patients with FOP. Strikingly, these FOP-causing variants imbue a neofunction to ACVR1 - the ability to recognize activin A as an agonist with bone morphogenic protein-like signaling that leads to heterotopic ossification (HO). These findings are su ...[more]

PMID: 35703179

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Project description:Fibrodysplasia ossificans progressiva (FOP) is a severely disabling heritable disorder of connective tissue characterized by congenital malformations of the great toes and progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites. The worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP. Children who have FOP appear normal at birth except for congenital malformations of the great toes. During the first decade of life, sporadic episodes of painful soft tissue swellings (flare-ups) occur which are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue. These flare-ups transform skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone, rendering movement impossible. Patients with atypical forms of FOP have been described. They either present with the classic features of FOP plus one or more atypical features [FOP plus], or present with major variations in one or both of the two classic defining features of FOP [FOP variants]. Classic FOP is caused by a recurrent activating mutation (617G>A; R206H) in the gene ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous ACVR1 missense mutations in conserved amino acids. The diagnosis of FOP is made by clinical evaluation. Confirmatory genetic testing is available. Differential diagnosis includes progressive osseous heteroplasia, osteosarcoma, lymphedema, soft tissue sarcoma, desmoid tumors, aggressive juvenile fibromatosis, and non-hereditary (acquired) heterotopic ossification. Although most cases of FOP are sporadic (noninherited mutations), a small number of inherited FOP cases show germline transmission in an autosomal dominant pattern. At present, there is no definitive treatment, but a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, may help reduce the intense inflammation and tissue edema seen in the early stages of the disease. Preventative management is based on prophylactic measures against falls, respiratory decline, and viral infections. The median lifespan is approximately 40 years of age. Most patients are wheelchair-bound by the end of the second decade of life and commonly die of complications of thoracic insufficiency syndrome.

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Twists in the fibrodysplasia ossificans progressiva story challenge and expand our understanding of BMP biology.

Publications

Twists in the fibrodysplasia ossificans progressiva story challenge and expand our understanding of BMP biology.

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