Alpha One Antitrypsin Deficiency: A Pulmonary Genetic Disorder

Alpha one antitrypsin protein (A1AT), is encoded on the SERPINA1 (serpin peptidase inhibitor, claude A, member 1 gene), (OMIM 107400), located on chromosome 14q32.1 and functions as inhibitor of the enzyme neutrophil elastase. People with a low serum level of this protein are described as having the alpha-1-antrypsin deficiency (A1ATD), (OMIM #613490), one of the most common heritable disorders. Having this disorder can predispose an individual to a variety of clinical diseases, with the lungs and the liver being the two organs most commonly affected. The A1AT protein is synthesized mainly in the liver by hepatocytes, secreted into the blood stream, and acts as an inhibitor of neutrophil elastase released primarily in the lung during inflammation. The most common allele for the SERPINA1 gene is named M (Middle), which encodes a normal A1AT protein identified in the middle on an isoelectric focusing gel. Over 120 allelic variants have been discovered and are named based on their position and movement on isoelectric gels, A-L if they exhibit faster migration than M, and N-Z if the proteins migrate more slowly. Rare mutations are often named after the discoverer or location of discover (Mmalton, Lowell, etc). A patient's genotype is notated as PI*Allele-Allele, and so patient homozygous for the wild-type A1AT protein is noted as being PI*M-M. The most common allelic variation causing clinical disease is the Z protein, manifesting most often in the setting of the genotype PI*Z-Z. This mutated protein spontaneously misfolds and then polymerizes with other misfolded A1AT proteins, becoming trapped in large quantities in the endoplasmic reticulum of liver hepatocytes. This results in liver inflammation and fibrosis, and can lead to clinically significant cholestasis and cirrhosis. Not all allelic variants of A1ATD cause liver damage, however, as some encode truncated proteins which do not misfold or polymerize. Rare null mutations have also been discovered due to point mutations that introduce a premature stop codon within the DNA sequence. Patients with the genotype PI*Null-Null do not develop liver disease because they do not synthesize mutated protein, but are at extremely high risk for the development of lung disease because of their inability to inhibit neutrophil elastase. In the case of the Z allele, the trapped protein is ineffectively secreted into the blood stream, resulting in a low serum concentration of A1AT. The mutated protein also has a reduced functional activity, making it a less effective inhibitor of neutrophil elastase. Without an appropriate level of functional A1AT in lung tissue, neutrophil elastase is free to break down elastin, a critical component of lung structure, which is thought to be the major