ACVR1 – Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare autosomal dominant disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of connective tissues. The causative gene, ACVR1, encodes Activin A receptor type I (ALK2), and heterozygous gain-of-function variants in ACVR1 define classic and variant FOP (PMID:19796185).

Genetic evidence demonstrates that the recurrent c.617G>A (p.Arg206His) mutation accounts for >95% of classic FOP cases across diverse populations, including Japanese, Italian, Chinese and Brazilian cohorts (PMID:17351709; PMID:18830232). A spectrum of additional missense variants—c.587T>C (p.Leu196Pro), c.619C>G (p.Gln207Glu), c.774G>C/T (p.Arg258Ser), c.772A>G (p.Arg258Gly), c.983G>A (p.Gly328Glu), and c.1123C>T (p.Arg375Cys)—has been reported in atypical or severe FOP presentations, often correlating with milder or more aggressive phenotypes (PMID:21044902; PMID:24852373). Approximately 700 patients have been described in the literature to date (PMID:31785620).

Segregation analyses reveal predominantly de novo occurrences of ACVR1 mutations, with rare instances of parental germline mosaicism and autosomal dominant transmission. Familial segregation was documented in five multi-generation kindreds for c.617G>A and c.983G>A variants, confirming co-segregation with FOP phenotype in affected relatives (PMID:19400542). No healthy carriers have been reported, supporting full penetrance of pathogenic alleles.

Functional studies elucidate a clear gain-of-function mechanism: the R206H mutant ACVR1 receptor signals constitutively through the BMP–SMAD1/5/8 axis in the absence of ligand, with augmented chondrogenesis and osteogenesis in cell lines, zebrafish and mouse models (PMID:19855136; PMID:23115204). Activin A aberrantly activates mutant ACVR1, driving heterotopic bone formation via an Activin-A/FOP-ACVR1/ENPP2/mTOR axis, and ACVR1-Fc fusion proteins or SMAD7 overexpression effectively inhibit this pathological signaling (PMID:28758906; PMID:27492611).

No robust conflicting evidence or refuting studies have been reported. ACVR1 variants outside FOP are associated with other ossification phenotypes (e.g., DISH) or non-skeletal disorders (e.g., DIPG), but these do not challenge the specific ACVR1–FOP relationship. Emerging genotype–phenotype correlations among variant alleles inform prognosis and potential targeted therapies.

Integration of genetic and experimental findings firmly establishes ACVR1 as the definitive FOP gene. Molecular diagnosis via targeted or broad sequencing of ACVR1 enables early confirmation, guides prenatal and preimplantation testing, and informs avoidance of iatrogenic triggers. Functional models provide platforms for preclinical testing of BMP pathway inhibitors, Activin A antibodies, and mTOR/AMPK modulators.

Key Take-home: Heterozygous gain-of-function mutations in ACVR1, most commonly c.617G>A (p.Arg206His), cause fibrodysplasia ossificans progressiva through constitutive BMP signaling and represent a definitive gene–disease pair with clear diagnostic and therapeutic implications.

References

• Clinical genetics • 2010 • Mutational screening of ACVR1 gene in Brazilian fibrodysplasia ossificans progressiva patients PMID:19796185
• Journal of human genetics • 2007 • The ACVR1 617G>A mutation is also recurrent in three Japanese patients with fibrodysplasia ossificans progressiva PMID:17351709
• European journal of human genetics • 2009 • Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements PMID:18830232
• Bone • 2011 • 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 PMID:21044902
• Human molecular genetics • 2014 • ACVR1 p.Q207E causes classic fibrodysplasia ossificans progressiva and is functionally distinct from the engineered constitutively active ACVR1 p.Q207D variant PMID:24852373
• Journal of clinical investigation • 2009 • The fibrodysplasia ossificans progressiva R206H ACVR1 mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization PMID:19855136
• Disease models & mechanisms • 2012 • Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis PMID:23115204
• Case reports in genetics • 2019 • Fibrodysplasia ossificans progressiva (stone man syndrome): a case report PMID:31785620
• The Journal of clinical investigation • 2017 • Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva PMID:28758906
• Bone • 2016 • ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva PMID:27492611

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