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Published on: December 18, 2019
An Acvr1 R206H knock-in mouse has fibrodysplasia ossificans progressiva
Salin A Chakkalakal1, Deyu Zhang, Andria L Culbert
1Department of Orthopaedic Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Abstract:
Fibrodysplasia ossificans progressiva (FOP; MIM #135100) is a debilitating genetic disorder of dysregulated cellular differentiation characterized by malformation of the great toes during embryonic skeletal development and by progressive heterotopic endochondral ossification postnatally. Patients with these classic clinical features of FOP have the identical heterozygous single nucleotide substitution (c.617G > A; R206H) in the gene encoding ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor. Gene targeting was used to develop an Acvr1 knock-in model for FOP (Acvr1(R206H/+)). Radiographic analysis of Acvr1(R206H/+) chimeric mice revealed that this mutation induced malformed first digits in the hind limbs and postnatal extraskeletal bone formation, recapitulating the human disease. Histological analysis of murine lesions showed inflammatory infiltration and apoptosis of skeletal muscle followed by robust formation of heterotopic bone through an endochondral pathway, identical to that seen in patients. Progenitor cells of a Tie2(+) lineage participated in each stage of endochondral osteogenesis. We further determined that both wild-type (WT) and mutant cells are present within the ectopic bone tissue, an unexpected finding that indicates that although the mutation is necessary to induce the bone formation process, the mutation is not required for progenitor cell contribution to bone and cartilage. This unique knock-in mouse model provides novel insight into the genetic regulation of heterotopic ossification and establishes the first direct in vivo evidence that the R206H mutation in ACVR1 causes FOP.
Insights
Fibrodysplasia ossificans progressiva (FOP) is caused by an ACVR1 mutation. A new mouse model shows this mutation triggers malformed digits and abnormal bone growth, confirming its role in FOP.
Area of Science:
- Genetics
- Developmental Biology
- Orthopedics
Background:
- Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder.
- It causes progressive heterotopic ossification and congenital malformations.
- A specific ACVR1/ALK2 gene mutation (R206H) is linked to FOP.
Purpose of the Study:
- To create and validate a mouse model for FOP.
- To investigate the role of the ACVR1 R206H mutation in FOP pathogenesis.
- To understand the cellular mechanisms of heterotopic ossification in FOP.
Main Methods:
- Gene targeting to create Acvr1 knock-in mice (Acvr1(R206H/+)).
- Radiographic and histological analysis of mutant mice.
- In vivo studies of cellular contributions to ectopic bone formation.
Main Results:
- The Acvr1(R206H/+) mouse model recapitulated FOP features, including malformed digits and heterotopic ossification.
- Histology revealed endochondral ossification in murine lesions, mirroring human FOP.
- Both wild-type and mutant cells contributed to ectopic bone, indicating the mutation initiates but doesn't solely drive the process.
Conclusions:
- The R206H mutation in ACVR1 is sufficient to cause FOP.
- The Acvr1(R206H/+) mouse is a valuable model for studying FOP and heterotopic ossification.
- This study provides direct in vivo evidence linking the ACVR1 R206H mutation to FOP pathogenesis.
