Genetic Variants of alpha(1)-Antitrypsin

alpha(1)-antitrypsin (alpha(1)-AT) is a 52 kDa sialoglycoprotein. The function of alpha(1)-antitrypsin is to protect the lower respiratory tract of lungs from proteolytic degradation by neutrophil elastase. Severe genetic deficiency of alpha(1)-AT is associated with early onset emphysema and liver diseases. alpha(1)-AT also exhibits anti-inflammatory activities independent of its protease inhibitor function. There are over 90 genetic variants of human alpha(1)-antitrypsin. These variants occur due to amino acid substitution / deletion which results in charge differences. Based on charge differences these variants have been identified by isoelectric focusing. The two most common deficiency variants are S and Z. The S variant migrates anodal to Z variant. The Z variant migrates most cathodal in isoelectric focusing, hence named Z. In Z variant, the sheet A undergoes expansion, therefore it can easily accept the reactive site loop of a second alpha(1)-AT molecule and consequently form polymers of alpha(1)-AT. These polymers of alpha(1)-AT aggregate in the hepatocytes and show liver and lungs diseases. Contrary to this, the S variant of alpha(1)-AT is not associated with any significant clinical disease because the conformation of the inhibitor is not altered significantly. The Z related pathologies could be treated by liver transplantation, augmentation therapy, gene therapy, peptide therapy and chemical chaperone therapy. In addition to common deficiency variants, there are several rare deficiency variants of alpha(1)-AT like Siiyama, Mmalton, Mprocida, Mheerlen, Mmineral springs, Mnichinan, Pduarte, Wbethesda Zaugsberg, and Zbristol. In Siiyama, Mmalton, Mnichinan and Zaugsberg, the sheet A is present in an open state, therefore these variants readily undergo polymerization and consequently show aggregation in the hepatocytes. In Mprocida, Mheerlen, Mmineral springs, Pduarte and Wbethesda the conformation is altered significantly, therefore these variants become conformationally less stable and thereby undergo intracellular proteolysis. These rare genetic variants show lungs and / or liver disease. There are several null variants of alpha(1)-AT that are not detected either at the stage of transcription or translation. The examples of some of the null variants are QOcardiff, QOhong kong, QOgranite falls, QObellingham, QOmattawa, QObolton, and QOludwigshafen. The molecular basis of deficiency of these variants also form the theme of this review.