The ABCA3 gene, located on chromosome 16, provides instructions for creating a protein produced almost exclusively in the lungs. This protein becomes embedded in the membranes of specific structures within lung cells. Its role is to manage the substances that allow the lungs to inflate and deflate with ease.
The gene’s instructions are used to form a substance that coats the inside of the lungs. This coating reduces surface tension, which prevents the delicate air sacs from sticking together when a person exhales. The proper function of this gene and its protein is directly linked to healthy lung function from the moment of birth.
The Function of the ABCA3 Gene
The ABCA3 gene’s function is carried out within specialized lung cells known as alveolar type II cells. These cells produce and manage pulmonary surfactant, a mixture of fats (phospholipids) and proteins that lines the lung’s air sacs, or alveoli. The ABCA3 protein is a transporter, moving phospholipids into cellular compartments called lamellar bodies. This action is a preparatory step for assembling the final surfactant mixture.
Lamellar bodies act as the storage and processing centers for surfactant components. The ABCA3 protein is part of the outer membrane of these structures, where it facilitates the import of lipids like phosphatidylcholine and phosphatidylglycerol. The formation of the lamellar bodies themselves also depends on the ABCA3 protein’s function.
Once fully formed and packaged, the surfactant is released into the alveolar space and spreads across the surface of the alveoli. This layer can be compared to a thin, slippery coating inside a balloon, allowing the alveoli to expand easily during inhalation and preventing them from collapsing upon exhalation. This entire system of surfactant production and secretion is a continuous cycle that supports every breath.
Understanding ABCA3 Mutations
A gene mutation is a change in the DNA sequence that provides instructions for making a protein. For the ABCA3 gene, a mutation can alter the protein’s structure and its ability to function. These changes range from minor alterations that slightly impair function to severe ones that prevent the protein from being made at all. Scientists have identified more than 200 different ABCA3 mutations associated with lung disease.
Health conditions from ABCA3 mutations are inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the mutated gene—one from each parent—to be affected. The parents themselves are carriers; they have one mutated copy and one normal copy of the gene. Carriers do not show symptoms because their one normal gene can produce enough functional protein.
When both parents are carriers of an ABCA3 mutation, there is a specific probability for their offspring with each pregnancy. There is a 25% chance of having an affected child with two mutated copies, a 50% chance of having a carrier child with one mutated copy, and a 25% chance of having an unaffected, non-carrier child.
Health Conditions Linked to ABCA3 Deficiency
When ABCA3 mutations cause a protein deficiency, pulmonary surfactant production is disrupted. This leads to a spectrum of lung diseases, with the severity depending on the specific mutations. The most severe forms manifest in newborns, while less severe mutations may result in lung disease that appears later in childhood or adulthood.
In full-term infants, mutations on both copies of the gene can cause severe neonatal respiratory distress syndrome (RDS). These newborns present with immediate breathing difficulties, including very rapid breathing (tachypnea), and require mechanical ventilation and high levels of oxygen. Unlike RDS in premature infants, this form is due to a defect in surfactant production and is often unresponsive to standard treatments.
Milder mutations can lead to childhood interstitial lung disease (chILD), a group of rare disorders affecting the tissue around the lung’s air sacs. The onset can be gradual, leading to chronic respiratory insufficiency. Symptoms include:
- Chronic coughing
- Rapid breathing
- Difficulty feeding
- Failure to grow and gain weight at a normal rate
Diagnosis and Management Strategies
Diagnosis of an ABCA3-related lung condition begins with a clinical evaluation of symptoms, followed by several specialized tests. Diagnostic tools include:
- High-resolution computed tomography (CT) scans of the chest, which may show characteristic patterns like ground-glass opacities.
- Bronchoscopy to collect fluid from the lungs for analysis.
- Genetic testing to identify the specific mutations in the ABCA3 gene, which provides a definitive diagnosis.
- A lung biopsy, which involves examining a small piece of lung tissue under a microscope and is considered a reliable diagnostic method.
Currently, there is no treatment that can fix the underlying genetic defect. Management strategies are supportive, aiming to alleviate symptoms and assist lung function. Common treatments include oxygen therapy, nutritional support to help children with poor growth, and medications like corticosteroids and hydroxychloroquine to manage lung disease.
The long-term outlook for individuals with ABCA3-related lung disease varies. Some may have a milder, chronic form of the disease that can be managed with supportive care. For those with severe, progressive respiratory failure that does not respond to other therapies, a lung transplant may be the only available long-term treatment option. This procedure carries its own risks and is reserved for the most serious cases.