Genes are the fundamental units of heredity, composed of DNA sequences that contain instructions for creating proteins. These proteins perform various functions and contribute to an organism’s traits and health. Understanding individual genes, such as ACVR1, helps explain how our bodies function and how genetic changes can lead to disease.
The ACVR1 Gene’s Normal Role
The ACVR1 gene, or Activin A Receptor Type I, provides instructions for making the ACVR1 protein. This protein is part of the bone morphogenetic protein (BMP) type I receptor family. These receptors are embedded in cell membranes, receiving external signals and transmitting them inward to influence cell development and function.
The ACVR1 protein is found in many bodily tissues, including skeletal muscle and cartilage. Its normal function involves regulating bone and muscle growth, particularly ossification, the process where cartilage is replaced by bone. This process is a natural part of skeletal maturation.
The ACVR1 protein is activated by specific signaling molecules, or ligands, such as bone morphogenetic proteins (BMPs) or activin A. When these ligands bind to the ACVR1 receptor, they trigger its activation. Another protein, FKBP12, can inhibit ACVR1, preventing inappropriate activation and ensuring balanced bone and tissue development.
When the ACVR1 Gene Goes Awry
Mutations in the ACVR1 gene can lead to Fibrodysplasia Ossificans Progressiva (FOP), a rare genetic disorder. FOP is characterized by heterotopic ossification, where bone abnormally forms in soft tissues like muscles, tendons, and ligaments. This process progressively locks joints, severely limiting movement and causing significant disability.
Individuals with FOP are often born with malformed big toes, an early indicator of the condition. Abnormal bone formation often begins in early childhood, starting in the neck and shoulders, then progressing downwards throughout the body. This new bone growth can occur spontaneously or be triggered by minor injuries, surgeries, or illnesses, leading to painful soft tissue swellings called “flare-ups” that eventually harden into bone.
FOP affects an estimated 1 in 2 million people worldwide. The disease’s progressive nature, with episodic flare-ups and irreversible bone formation, restricts range of motion and severely impacts quality of life. Challenges include difficulty eating and speaking if bone forms around the mouth, and breathing difficulties if extra bone growth restricts the rib cage, potentially leading to respiratory infections or heart failure.
Understanding the Impact of ACVR1 Mutations
The most common ACVR1 mutation, found in over 95% of FOP cases, involves a specific change at position 206 of the ACVR1 protein: arginine is replaced by histidine (R206H). This is considered a “gain-of-function” mutation.
A gain-of-function mutation means the mutated ACVR1 gene becomes overactive, or “always on,” even without its usual activating signals. This leads to uncontrolled bone formation. The ACVR1 protein normally functions within the bone morphogenetic protein (BMP) signaling pathway, which regulates bone and tissue development. With the mutation, the BMP pathway becomes excessively activated, causing soft tissue cells to differentiate into cartilage and then bone.
The R206H mutation in ACVR1 causes the receptor to be constantly active, even in the absence of its usual ligands. It also enhances the receptor’s responsiveness to certain ligands, such as activin A, which normally triggers a different signaling pathway. This aberrant signaling drives the pathological bone formation seen in FOP.
Current Research and Future Treatments
Research into the ACVR1 gene and FOP focuses on developing effective treatments. One promising approach involves drug development, particularly inhibitors targeting the overactive ACVR1 protein or the broader BMP signaling pathway. For instance, palovarotene, a retinoid receptor gamma agonist, has received approval for treating FOP and aims to reduce new bone formation.
Other investigational therapies include saracatinib, which has shown promise in inhibiting heterotopic ossification in mouse models of FOP and is currently in clinical trials. Researchers are also exploring antibodies that block activin A, a ligand that abnormally activates the mutated ACVR1 receptor in FOP patients. Inhibiting activin A has suppressed heterotopic ossification in FOP mouse models.
Gene therapy approaches are also under investigation due to FOP’s consistent genetic cause. These strategies aim to suppress mutant ACVR1 alleles without affecting the normal gene. Research goals include slowing bone formation, preventing painful flare-ups, and improving quality of life for individuals with FOP.