Molecular mechanisms of alpha1-antitrypsin null alleles

Alpha1-antitrypsin (alpha1-AT) is the most abundant circulating inhibitor of serine proteases and therefore is essential to normal protease-anti-protease homeostasis. Inheritance of two parental alpha1-AT deficiency alleles is associated with a substantially increased risk for development of emphysema and liver disease. In very rare circumstances individuals may inherit alpha1-AT null alleles. Null alpha1-AT alleles are characterized by the total absence of serum alpha1-AT. These alleles represent the extreme end in a continuum of alleles associated with alpha1-AT deficiency. The molecular mechanisms responsible for absence of serum alpha1-AT include splicing abnormalities, deletion of alpha1-AT coding exons and premature stop codons. While these alleles comprise only a small proportion of alpha1-AT alleles associated with profound alpha1-AT deficiency, studies of their molecular mechanisms provide valuable insights into the structure, gene expression and intracellular transport of alpha1-AT.