The SERPINA1 gene provides instructions for a protective protein in the body. It defends against damage, particularly in sensitive tissues like the lungs. Understanding this gene and its protein helps explain its impact on health.
What is SERPINA1? Understanding the Gene and its Protein
The SERPINA1 gene, short for serpin family A member 1, produces a protein called Alpha-1 Antitrypsin (AAT). This protein is produced mainly in the liver and circulates in the bloodstream. AAT is a serine protease inhibitor (serpin) that regulates enzyme activities.
AAT prevents tissue damage by inhibiting enzymes, especially neutrophil elastase. Neutrophil elastase is an enzyme released by white blood cells during infection or inflammation to break down harmful substances. AAT neutralizes neutrophil elastase, preventing it from breaking down healthy tissues, particularly in the lungs. Without sufficient AAT, this enzyme can act unchecked, causing widespread cellular destruction.
When SERPINA1 Doesn’t Work: Alpha-1 Antitrypsin Deficiency
When the SERPINA1 gene does not function correctly, it leads to Alpha-1 Antitrypsin Deficiency (AATD). This inherited disorder occurs due to specific mutations or variants in the gene. Over 100 different variants have been identified, with some leading to insufficient AAT production or abnormal AAT proteins.
For instance, the common Z allele results from a change where glutamic acid is replaced by lysine at protein position 342, leading to very low AAT levels. The S allele involves a glutamic acid to valine substitution at position 264, causing moderately low AAT levels. These genetic alterations mean the body produces too little functional AAT or AAT that cannot properly leave the liver, leaving tissues vulnerable to damage.
Health Conditions Linked to SERPINA1 Deficiency
Alpha-1 Antitrypsin Deficiency primarily impacts the lungs and liver, leading to distinct complications. In the lungs, insufficient AAT allows neutrophil elastase to continuously break down elastin and collagen in the alveolar walls, causing progressive damage. This unchecked activity leads to emphysema, where the small air sacs (alveoli) are irreversibly damaged. Symptoms include shortness of breath, wheezing, and a chronic cough.
Lung problems often manifest between 20 and 50 years of age. Smoking or exposure to environmental dust can accelerate the onset and progression of lung disease.
The liver can also be affected because abnormal AAT proteins, particularly those from the Z allele, may accumulate within its cells. This buildup can cause inflammation and scarring, potentially leading to liver damage, cirrhosis, and hepatocellular carcinoma (a type of liver cancer). Approximately 10% of infants with AATD develop liver disease, often presenting as jaundice. About 15% of adults may experience cirrhosis. Less commonly, AATD can cause necrotizing panniculitis, a skin condition with painful, hardened lumps or patches.
Diagnosing and Managing SERPINA1 Deficiency
Diagnosing Alpha-1 Antitrypsin Deficiency often begins with blood tests to measure AAT protein levels. If these levels are lower than expected, genetic testing (genotyping or phenotyping) can confirm the diagnosis by identifying specific SERPINA1 gene mutations. Since AATD symptoms can resemble common conditions like asthma or COPD, diagnosis can be delayed. Testing is recommended for individuals with unexplained lung disease, liver disease, or a family history of AATD.
Management of AATD aims to reduce symptoms and slow disease progression, as there is no cure. Augmentation therapy is a treatment for lung disease where AAT protein, purified from healthy donors, is given intravenously, often once a week, to increase AAT levels in the blood. While this therapy does not reverse existing lung damage, it may help preserve lung function and reduce lung infections. Lifestyle adjustments are also important, including avoiding smoking and exposure to lung irritants (dust, pollution), and minimizing alcohol consumption to protect the liver. Symptomatic treatments like bronchodilators, inhaled corticosteroids, and pulmonary rehabilitation programs may also be used to manage lung symptoms.