Molecular mechanisms of alpha1-antitrypsin null alleles

Abstract

Alpha1-antitrypsin (α1-AT) is the most abundant circulating inhibitor of serine proteases and therefore is essential to normal protease-anti-protease homeostasis. Inheritance of two parental α1-AT deficiency alleles is associated with a substantially increased risk for development of emphysema and liver disease. In very rare circumstances individuals may inherit α1-AT null alleles. Null α1-AT alleles are characterized by the total absence of serum α1-AT. These alleles represent the extreme end in a continuum of alleles associated with α1-AT deficiency. The molecular mechanisms responsible for absence of serum α1-AT include splicing abnormalities, deletion of α1-AT coding exons and premature stop codons. While these alleles comprise only a small proportion of α1-AT alleles associated with profound α1-AT deficiency, studies of their molecular mechanisms provide valuable insights into the structure, gene expression and intracellular transport of α1-AT.