ABSTRACT
The primary defect in alpha 1-antitrypsin (alAT) deficiency resides with the hepatocyte. Current concepts suggest that a single amino acid substitution in the PiZ allele (Glu 342 to Lys 342) produces structural changes that impair posttranslational processing of the nascent alAT protein. One hypothesis is that the loss of an internal salt bridge ( 1) or simply the addition of positive charge itself (2) leads to disturbed protein-folding, which further impairs posttranslational pro cessing and subsequent secretion of the protein. The net result is a slowing of the release of the molecule such that in PiZ deficiency only about 10-15% of the normal amount is released. Importantly, the protein that does get released has a normal half-life and is functional as an antiprotease (3,4). Therefore, a logical approach to therapy for alAT deficiency is to correct the primary defect, i.e., the impaired hepatocyte release. In principle, correcting this defect could both allevi ate the risk of hepatocellular injury (which is likely related to the “storage disorder” itself) and provide protection against accelerated emphysema.
