ACAN Gene: Function, Mutations, and Related Conditions

The ACAN gene provides the instructions for a protein essential for the body’s skeletal framework, directing a core component for the healthy development of cartilage and bone. Its role is prominent during early development when the skeleton is first forming.

The Role of Aggrecan in the Body

The protein produced from the ACAN gene is called aggrecan, the most plentiful proteoglycan in cartilage. This tough, flexible tissue covers the ends of bones for protection. Aggrecan is a major component of the extracellular matrix, which provides structural support to surrounding cells.

Aggrecan’s structure resembles a bottlebrush, with sugar chains known as glycosaminoglycans (GAGs) attached to a protein core. These chains attract and hold water, turning cartilage into a hydrated, gel-like substance. When a joint moves, the cartilage compresses and releases water, then reabsorbs it as pressure eases. This sponge-like action allows cartilage to function as a shock absorber, protecting joints from impact.

Aggrecan is also important for bone development. During childhood, it is abundant in the growth plates, areas of cartilage at the ends of long bones where new growth occurs. Aggrecan helps organize this cartilaginous framework, which is converted into bone through a process called ossification.

Conditions Associated with ACAN Gene Mutations

Mutations within the ACAN gene disrupt the production of the aggrecan protein, leading to skeletal disorders. These conditions impact cartilage and bone development, causing varied but related symptoms. The type and severity of the disorder depend on how the specific mutation affects the aggrecan protein.

A primary condition is Spondyloepiphyseal Dysplasia, ACAN-related (SEMD). This skeletal dysplasia affects bone formation in the spine (spondylo-) and the ends of long bones (epiphyseal). Individuals with this condition have a disproportionately short stature, with a trunk shorter than their limbs. They also experience joint problems and may develop early-onset osteoarthritis.

Another condition linked to ACAN mutations is familial Osteochondritis Dissecans (OCD). This disorder involves the separation of cartilage and underlying bone from the end of a bone at a joint, causing pain and instability. In its familial form, individuals may have lesions in multiple joints, such as the knees, elbows, and ankles. Affected individuals often present with short stature and premature osteoarthritis.

Certain ACAN gene variants are also associated with less severe forms of short stature, sometimes called idiopathic short stature. Individuals have a height below average but may not show the pronounced skeletal abnormalities seen in SEMD or OCD. This demonstrates that ACAN-related disorders exist on a spectrum from severe skeletal dysplasias to milder conditions.

Inheritance and Genetic Testing

Disorders from ACAN gene mutations are passed down in an autosomal dominant pattern. This means inheriting only one copy of the altered gene from one parent causes the condition. A parent with the mutation has a 50% chance of passing it to each child.

In some cases, the condition results from a new mutation in the ACAN gene, known as a de novo mutation. This occurs in individuals with no family history of the disorder.

Genetic testing provides a definitive diagnosis for an ACAN-related condition. The process involves analyzing a DNA sample from blood or saliva to find mutations in the ACAN gene sequence. Identifying a specific variant confirms the diagnosis and helps predict the condition’s course. Genetic counseling helps families understand the diagnosis and inheritance pattern.

Management of Related Health Issues

There is no cure for the underlying genetic defect in ACAN-related disorders, so medical management focuses on addressing symptoms and improving quality of life. The approach is multidisciplinary, involving specialists in orthopedics, physical therapy, and pain management for a comprehensive care plan.

Orthopedic monitoring is a primary component of management. Regular check-ups, including imaging studies like X-rays, are used to track spine health, joint integrity, and skeletal development. This monitoring allows for the early detection of issues like scoliosis, joint misalignments, or osteoarthritis, enabling timely interventions.

Physical therapy is important for maintaining joint function and mobility. Exercises are designed to strengthen the muscles supporting the joints, which reduces stress on the compromised cartilage. Maintaining a healthy weight is also emphasized to lessen the load on joints like the hips and knees. Pain management may include over-the-counter anti-inflammatory medications or other prescriptions for chronic joint pain.

When joint damage becomes severe, surgical intervention may be considered to improve mobility and pain. Procedures can range from arthroscopic surgery to repair cartilage lesions to total joint replacement for end-stage osteoarthritis. The decision to pursue surgery depends on the individual’s symptoms, age, and overall health.