Molecular Genetics Of Fibrodysplasia Ossificans Progressiva

Leo Migdal

-Dec 5, 2025, 4:39 PM

molecular genetics of fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense mutations in the ACVR1 gene, this disorder has hitherto defied comprehensive mechanistic understanding and effective treatment paradigms. This write-up offers a comprehensive overview of the contemporary understanding of FOP's complex pathobiology, underscored by advances in molecular genetics and proteomic studies. We delve into targeted therapy, spanning genetic therapeutics, enzymatic and transcriptional modulation, stem cell therapies, and innovative immunotherapies. We also highlight the intricate complexities surrounding clinical trial design for ultra-rare disorders like FOP, addressing fundamental statistical limitations, ethical conundrums, and methodological advancements essential for the success of interventional studies.

We advocate for the adoption of a multi-disciplinary approach that converges bench-to-bedside research, clinical expertise, and ethical considerations to tackle the challenges of ultra-rare diseases like FOP and comparable ultra-rare diseases. In essence, this manuscript serves a dual purpose: as a definitive scientific resource for ongoing and future FOP research and a call to action for innovative solutions to address methodological and ethical challenges that... Keywords: ACVR1; antisense therapy; bone morphogenetic proteins (BMPs); clinical trial design for ultra-rare diseases; fibrodysplasia ossificans progressiva (FOP); genetic therapy; heterotopic ossification; targeted therapy; ultra-rare disorders. T.Y. is a co-founder and shareholder of OligomicsTx Inc., which aims to commercialize antisense technology. S.A.

declares that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. Schematic overview of the human ACVR1 gene, its molecular architecture, and mutational landscape… Canonical and aberrant BMP signaling and FOP. The canonical and aberrant activin A-mediated… Correspondence: frederick.kaplan@pennmedicine.upenn.edu Received 2024 Jun 25; Revised 2024 Aug 12; Accepted 2024 Aug 13; Collection date 2024 Aug.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). When a genetic disease is characterized by the abnormal activation of normal molecular pathways and cellular events, it is illuminating to critically examine the places and times of these activities both in health and... Therefore, because heterotopic ossification (HO) in fibrodysplasia ossificans progressiva (FOP) is by far the disease’s most prominent symptom, attention is also directed toward the pathways and processes of bone formation during skeletal development. FOP is recognizable by effects of the causative mutation on skeletal development even before HO manifests, specifically in the malformation of the great toes. This signature skeletal phenotype is the most highly penetrant, but is only one among several skeletal abnormalities associated with FOP.

Patients may present clinically with joint malformation and ankylosis, particularly in the cervical spine and costovertebral joints, as well as characteristic facial features and a litany of less common, non-skeletal symptoms, all stemming from... In the same way that studying the genetic cause of HO advanced our understanding of HO initiation and progression, insight into the roles of ACVR1 signaling during tissue development, particularly in the musculoskeletal system,... This review will detail what is known about the molecular mechanisms of developmental phenotypes in FOP and the early role of ACVR1 in skeletal patterning and growth, as well as highlight how better understanding... Keywords: FOP, ACVR1, skeletal development, joint development, BMP, digit patterning First prospective study to assess the association of fibrodysplasia ossificans progressive (FOP) flare-ups and extra-skeletal bone growth (heterotopic ossification or HO) with functional impairment PARIS, France, 28 September 2022 – Ipsen (Euronext: IPN; ADR: IPSEY) today announced the publication of its Natural History Study (NHS) of FOP in Genetics in Medicine, the official journal of the American College...

This is the first time a global, prospective, longitudinal evaluation of FOP has been carried out, with data collected over a period of 36 months. Findings demonstrated the debilitating impact and progressive nature of the disease, with the greatest progression of new heterotopic ossification (HO; or bone growth that takes place outside of the normal skeletal system in joints... “Natural history studies are essential to understanding ultra-rare diseases with high unmet need like FOP, increasing our knowledge around the natural course of disease, diagnoses, monitoring techniques, potential biomarkers and new outcome measures,” said... Robert Pignolo, Professor of Geriatric Medicine, Mayo Clinic, USA. “This is the first study of its kind following the progression of FOP over three years. These results demonstrate the significant impact of the disease on people living with FOP.

Furthermore, it will facilitate the evaluation of meaningful endpoints in the development of new therapies, which are critically needed for individuals with FOP.” Results from the NHS demonstrated at month 36, across the whole study population, a mean of 2.6 body regions with new HO; this was highest (3.9) in those aged between two and eight years... However, although individuals aged 25 – 65 years had the lowest new HO volume at annual visits, approximately 70% continued to accumulate new HO across the duration of the study. These data confirmed the progressive nature of FOP with characteristic patterns of growth, starting in younger individuals initially across the upper and mid-torso, progressing into hip and lower-leg regions, and with accumulation of HO... The assessment of flare-ups showed, 82 (71.9%) individuals experienced a total of 229 flare-ups, most commonly in the upper back (17.9%), hip (14.8%) and shoulder (10.9%). Individuals between the ages of two and eight years, were most likely to report more than one flare-up throughout the study duration.

For those who experienced flare-ups, the most common symptoms were pain and soft tissue swelling. Imaging at the site of the flare-up revealed HO occurring at the time of the flare-up, with many individuals going on to experience new HO in the following 12 weeks.1 Fibrodysplasia ossificans progressiva (FOP; OMIM #135100) is a rare genetic disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues. To date, the disease has been linked to 15 pathogenic variants in the ACVR1 gene, which encodes a type I receptor for bone morphogenetic proteins. Most patients with FOP carry a recurrent single-nucleotide substitution (c.617G>A; p.Arg206His) in the ACVR1 gene. The genotype-phenotype correlations for atypical pathogenic variants of ACVR1 are poorly understood.

In this study, we report the largest population of Polish patients affected by FOP and analyze their phenotypes and genotypes. We screened the whole ACVR1 coding sequence of 16 patients affected by FOP to confirm the presence of pathogenic variants. Thirteen individuals carried the classic pathogenic variant (p.Arg206His) and had a classic or FOP-plus phenotype. In agreement with the findings of previous studies, one patient with a p.Gly356Asp pathogenic variant had a variant FOP phenotype. We point to an unusual phenomenon in two patients who carried atypical pathogenic variants (p.Gly356Asp and p.Arg258Ser) and displayed a classic FOP phenotype. Our study extends the understanding of FOP's genotype-phenotype correlation, suggesting that classic FOP phenotypes are associated with non-classic pathogenic variants.

We also summarize the recent advances in drug development for this condition. Therefore, the study may be valuable for clinicians consulting patients with FOP. Keywords: Activin A type I receptor gene (ACVR1); Bone morphogenetic protein (BMP); Genotype–phenotype correlations; Heterotopic ossification; Treatment strategies. Declarations. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of the Poznan University of Medical Sciences ethics committee.

Consent to participate: Informed consent was obtained from all individual participants included in the study, while the parents consented on behalf of the index patient. Consent for publication: The authors affirm that the patients provided informed consent to publish the images in Fig. 4. Competing interests: The authors declare no competing interests.

Molecular Genetics Of Fibrodysplasia Ossificans Progressiva

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