SERPINA1

The SERPINA1 gene provides instructions for making a protein called alpha-1 antitrypsin, which is a type of serpin protein. Serpin proteins help to control several types of chemical reactions by inhibiting certain enzymes. Alpha-1 antitrypsin got its name because it inhibits the digestive enzyme trypsin. It also inhibits other enzymes including neutrophil elastase, a powerful enzyme found in white blood cells.

Alpha-1 antitrypsin is mainly produced in the liver, and then it is transported to the lungs via the blood. It protects lung tissue from being damaged by the enzyme neutrophil elastase. This enzyme fights infection when released from white blood cells, but it can attack and damage lung tissue if not controlled by alpha-1 antitrypsin.

alpha-1 antitrypsin deficiency - caused by mutations in the SERPINA1 gene

More than 120 SERPINA1 mutations have been identified. While some mutations are harmless, others cause a moderate to severe shortage (deficiency) of alpha-1 antitrypsin, which reduces protection against the powerful neutrophil elastase enzyme. Uncontrolled, neutrophil elastase can destroy small air sacs in the lungs (alveoli). Continued damage to the alveoli can lead to emphysema, an irreversible disease that causes extreme shortness of breath.

Many SERPINA1 mutations change one of the protein building blocks (amino acids) used to make alpha-1 antitrypsin. One of the most common mutations replaces the amino acid glutamic acid with the amino acid lysine at protein position 342 (written as Glu342Lys or E342K). This particular mutation and other mutations that change amino acids alter the structure of alpha-1 antitrypsin. As a result, multiple alpha-1 antitrypsin proteins may bind together to form a large molecule, or polymer, that cannot be exported from the liver. Liver tissue can be damaged as these polymers accumulate, and lung tissue is destroyed because too little alpha-1 antitrypsin is exported from the liver to protect against neutrophil elastase. Research indicates that these polymers may contribute to excessive inflammation, which may explain other features of alpha-1 antitrypsin deficiency such as a skin condition called panniculitis.

Other SERPINA1 mutations lead to an abnormally small form of alpha-1 antitrypsin, which is quickly broken down in the liver. As a result, little or no alpha-1 antitrypsin is exported to the lungs. With this type of mutation, the liver remains healthy, but the lungs are left unprotected against neutrophil elastase.