Cause Of Fibrodysplasia Ossificans Progressiva Research Articles

Fibrodysplasia Ossificans Progressiva: Molecular Mechanism, Drug Development and Current Clinical Trials

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic human disease characterized by abnormal bone formation in muscle and soft tissues of the patient, due to dysregulated activity of the bone morphogenetic protein (BMP) signaling. Activin A receptor type I (ACVR1), also known as Activin-like kinase 2 (ALK2), is a key BMP type I receptor for the normal BMP signaling transduction. The heterozygous missense mutations in ALK2 are the root cause of FOP, and ALK2R206H accounts for approximately 97% of all FOP cases. Cumulative studies have shown that Activin A, which normally activates TGF - β signaling, can induce the BMP signaling via ALK2 mutated receptor in FOP. In the past decade, multiple therapeutical strategies have been developed and several potential drugs are under clinical trials for FOP now. This article specifically focuses on the recent progress in understanding the molecular mechanism, potential drug development and the clinical trials for FOP treatment.

Induced Pluripotent Stem Cells to Model Human Fibrodysplasia Ossificans Progressiva

SummaryFibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by progressive ossification of soft tissues, for which there is no effective treatment. Mutations in the bone morphogenetic protein (BMP) type I receptor activin receptor-like kinase 2 (ACVR1/ALK2) are the main cause of FOP. We generated human induced pluripotent stem cells (hiPSCs) from FOP patients with the ALK2 R206H mutation. The mutant ALK2 gene changed differentiation efficiencies of hiPSCs into FOP bone-forming progenitors: endothelial cells (ECs) and pericytes. ECs from FOP hiPSCs showed reduced expression of vascular endothelial growth factor receptor 2 and could transform into mesenchymal cells through endothelial-mesenchymal transition. Increased mineralization of pericytes from FOP hiPSCs could be partly inhibited by the ALK2 kinase inhibitor LDN-212854. Thus, differentiated FOP hiPSCs recapitulate some aspects of the disease phenotype in vitro, and they could be instrumental in further elucidating underlying mechanisms of FOP and development of therapeutic drug candidates.

Antisense-Oligonucleotide Mediated Exon Skipping in Activin-Receptor-Like Kinase 2: Inhibiting the Receptor That Is Overactive in Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disease characterized by progressive heterotopic ossification of connective tissues, for which there is presently no definite treatment. A recurrent activating mutation (c.617G→A; R206H) of activin receptor-like kinase 2 (ACVR1/ALK2), a BMP type I receptor, has been shown as the main cause of FOP. This mutation constitutively activates the BMP signaling pathway and initiates the formation of heterotopic bone. In this study, we have designed antisense oligonucleotides (AONs) to knockdown mouse ALK2 expression by means of exon skipping. The ALK2 AON could induce exon skipping in cells, which was accompanied by decreased ALK2 mRNA levels and impaired BMP signaling. In addition, the ALK2 AON potentiated muscle differentiation and repressed BMP6-induced osteoblast differentiation. Our results therefore provide a potential therapeutic approach for the treatment of FOP disease by reducing the excessive ALK2 activity in FOP patients.

Role of Altered Signal Transduction in Heterotopic Ossification and Fibrodysplasia Ossificans Progressiva

Heterotopic ossification is a pathologic condition in which bone tissue is formed outside of the skeleton, within soft tissues of the body. The extraskeletal bone that forms in these disorders is normal; the cellular mechanisms that direct cell fate decisions are dysregulated. Patients with fibrodysplasia ossificans progressiva (FOP), a rare human genetic disorder of extensive and progressive heterotopic ossification, have malformations of normal skeletal elements, identifying the causative gene mutation and its relevant signaling pathways as key regulators of skeletal development and of cell fate decisions by adult stem cells. The discovery that mildly activating mutations in ACVR1/ALK2, a bone morphogenetic protein (BMP) type I receptor, is the cause of FOP has provided opportunities to identify previously unknown functions for this receptor and for BMP signaling and to develop new diagnostic and therapeutic strategies for FOP and other more common forms of heterotopic ossification, as well as tissue engineering applications.

Mutational screening of ACVR1 gene in Brazilian fibrodysplasia ossificans progressiva patients

Fibrodysplasia ossificans progressiva (FOP) is a severe genetic disorder reported worldwide. A specific heterozygous mutation (c.617G> A; p.R206H) in the activin A type I receptor gene (ACVR1) is regarded as the genetic cause of FOP in all classically affected individuals worldwide. However, a few patients with FOP variants harbor distinct mutations in ACVR1. We screened a group of FOP Brazilian population for mutations in ACVR1. Of 16 patients with a classic FOP phenotype (10 males and 6 females, age range of 3-42 years), all had the classic mutation (p.R206H). One 21-year-old woman with a variant FOP phenotype had the previously reported c.983G> A mutation (p.G328E). Our study contributes to the understanding of the predominant FOP phenotype and genotype and suggests that variant FOP phenotypes are associated with specific mutations in ACVR1 gene.

Mutation Analysis and Prenatal Exclusion of Fibrodysplasia Ossificans Progressiva in a Chinese Fetus.

Aims: Fibrodysplasia ossificans progressiva (FOP) is a rare and severely disabling autosomal dominant disorder characterized by congenital malformations of the great toes and progressive postnatal heterotopic ossification. A point mutation in the activin receptor IA (ACVR1) gene is the cause of FOP. Most of the reported cases of FOP are sporadic and caused by de novo mutations; however, some rare cases can also result from parental germline mosaicism associated with a greater risk of recurrence in successive pregnancies. Therefore, once the pathogenic mutation has been identified in the proband, it is relative cheaper and important to perform prenatal diagnostic tests to exclude the recurrence risk of FOP in subsequent pregnancies. In this study, we first investigated the mutation in the ACVR1 gene in a Chinese FOP patient and then performed prenatal tests to exclude the risk of recurrence in the patient's unborn sibling. Methods: A couple visited our clinic with their 4-year-old son, who was clinically diagnosed with FOP, for genetic counseling. Genetic testing was performed by amplifying all the nine exons of the ACVR1 gene using the conventional polymerase chain reaction. Further, DNA sequencing was used to determine the mutation based on the results of a mutation screening using denaturing high-performance liquid chromatography. Subsequently, a prenatal test was performed using the same technique as that used for the proband. Results: A recurrent single nucleotide mutation c.617 G>A (R206H) of the ACVR1 gene was identified in the patient; however, both the parents had a normal ACVR1 gene. Prenatal tests showed that the fetus did not carry the pathogenic mutation. Conclusion: The results confirmed that a recurrent single nucleotide mutation c.617 G>A (R206H) was the genetic cause of FOP and explored the utility of prenatal testing in excluding the risk of recurrence in the successive pregnancy.

Early Diagnosis of Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva is a rare and disabling genetic condition characterized by congenital malformation of the great toes and by progressive heterotopic ossification in specific anatomic patterns. Most patients with fibrodysplasia ossificans progressiva are misdiagnosed early in life before the appearance of heterotopic ossification and undergo diagnostic procedures that can cause lifelong disability. Recently, the genetic cause of fibrodysplasia ossificans progressiva was identified, and definitive genetic testing for fibrodysplasia ossificans progressiva is now available before the appearance of heterotopic ossification. We recently evaluated 7 children for diagnosis of fibrodysplasia ossificans progressiva before the onset of heterotopic ossification. A medical history, physical examination, and skeletal survey were obtained on all of the patients, as well as clinical genetic testing for the canonical fibrodysplasia ossificans progressiva mutation. All 7 of the children (4 girls and 3 boys; ages 3 months to 6 years) had congenital malformations of the great toes, but none had radiographic evidence of heterotopic ossification at the time of evaluation. Five of the 7 children had soft tissue lesions of the neck and back, suggestive of early fibrodysplasia ossificans progressiva flare-ups, 3 of whom had undergone invasive diagnostic procedures that exacerbated their condition. Two children had no history or signs of soft tissue swelling or flare-ups. DNA sequence analysis found that all 7 of the children had the recurrent fibrodysplasia ossificans progressiva missense mutation, a single nucleotide substitution (c.617G>A) at codon 206 in the glycine-serine activation domain of activin receptor IA, a bone morphogenetic protein type 1 receptor. Clinical suspicion of fibrodysplasia ossificans progressiva early in life on the basis of malformed great toes can lead to early clinical diagnosis, confirmatory diagnostic genetic testing, and the avoidance of additional harmful diagnostic and treatment procedures. This is the first report of genetic confirmation of fibrodysplasia ossificans progressiva before the appearance of heterotopic ossification. Pediatricians should be aware of the early diagnostic features of fibrodysplasia ossificans progressiva, even before the appearance of heterotopic ossification. This awareness should prompt early genetic consultation and testing and the institution of assiduous precautions to prevent iatrogenic harm.

Lumbar puncture and surgical intervention in a child with undiagnosed fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare, autosomal dominant disorder characterized by congenital malformation of the great toes and episodes of soft tissue swelling that lead to progressive heterotopic ossification. The genetic cause of FOP was recently discovered to be a recurrent missense activating mutation in the activin A type I receptor, a bone morphogenetic protein type I receptor in all classically affected individuals worldwide. The authors present a child with the classic features of previously undiagnosed FOP who developed a paraspinal soft-tissue mass after a lumbar puncture for a fever workup. Excision of the mass resulted in a massive inflammatory response leading to progression of heterotopic ossification. Awareness of the classic clinical features of FOP prior to the appearance of heterotopic ossification can prompt early clinical diagnosis and confirmation through genetic testing, thus avoiding interventions that lead to irreversible iatrogenic harm.

Fibrodysplasia Ossificans Progressiva and Progressive Osseous Heteroplasia: <I>Two Genetic Disorders of Heterotopic Ossification</I>

Heterotopic ossification (HO) as a primary clinical finding is uncommon, but it occurs in two human genetic disorders: fibrodysplasia ossific, ans progressiva (FOP) and progressive osseous heteroplasia (POH). In these disorders, the progression and stages of the ectopic bone formation appear normal, but disregulation of cell differentiation leads to improper induction of bone formation—in other words, normal bone forms in the wrong place at the wrong time. Cases of POH were initially recognized following misdiagnosis as FOP. However, POH can be distinguished from FOP by several criteria: the presence of cutaneous ossification, the absence of congenital malformations of the skeleton, the absence of inflammatory tumor-like swellings, the asymmetric mosaic distribution of lesions, the absence of predictable regional patterns of HO, and the predominance of intramembranous rather than endochondral ossification. Both FOP and POH are rare conditions, with most cases apparently the result of a de novo (spontaneous) mutation: however, when inherited, both are transmitted through an autosomal-dominant inheritance pattern. Although FOP can be inherited from either a mother or a father, POH is only inheried paternally. Consistent with this parental inheritance pattern, POH patients carry inactivating mutations of the GNAS gene, a gene that is regulated through genomic imprinting and allele-specific gene expression. The genetic cause of FOP remains undetermined. A combination of clinical and genetic evaluations can identify FOP and POH, two distinct disorders of extensive HO.

Fibrodysplasia Ossificans Progressiva Why Do Some People Have Two Skeletons?

Fibrodysplasia ossificans progressiva (FOP) is one of the rarest genetic conditions known. People who have this disorder essentially form two skeletons: a normal one during embryogenesis and a heterotopic one after birth. Although the general phenotype of the disease, including the presence of congenital malformations of the great toes, is constant among individuals, there is wide variation in the severity of the disorder. Studies to identify the cause of FOP currently are focused on a candidate gene approach. Bone morphogenetic proteins (BMPs) are bone-inducing morphogens that are involved in the developmental organization of the skeleton and are excellent candidate genes for disorders of heterotopic osteogenesis. We recently have demonstrated that overexpression of BMP 4 in cells from patients who have FOP is associated with this disorder. We are continuing to investigate the role of BMP-4 in the pathophysiology of FOP. An analysis of the genetic and cellular pathways that are activated ectopically in patients who have FOP will help elucidate how bone forms and grows and will lead to more effective treatments of orthotopic and heterotopic osteogenesis.