A naturally occurring nonpolymerogenic mutant of alpha 1-antitrypsin characterized by prolonged retention in the endoplasmic reticulum

The classical form of alphal-antitrypsin (alphal-AT) deficiency is associat ed with a mutant alpha1-ATZ molecule that polymerizes in the endoplasmic re ticulum (ER) of liver cells. A subgroup of individuals homozygous for the p rotease inhibitor (PI) Z allele develop chronic liver injury and are predis posed to hepatocellular carcinoma. In this study we evaluated the primary s tructure of alphal-AT in a family in which three affected members had sever e liver disease associated with alphal-AT deficiency. We discovered that on e sibling was a compound heterozygote with one PI Z allele and a second all ele, the PI Z + saar allele, bearing the mutation that characterizes alphal -ATZ as well as the mutation that characterizes alphal-AT Saarbrucken (alph al-AT saar). The mutation in PI saar introduces a premature termination cod on resulting in an alphal-AT protein truncated for 19 amino acids at its ca rboxyl terminus. Studies of a second sib with severe liver disease and othe r living family members did not reveal the presence of the alphal-AT saar m utation and therefore do not substantiate a role for this mutation in the l iver disease phenotype of this family. However, studies of alphal-AT saar a nd alphal-ATZ + saar expressed in heterologous cells show that there is pro longed intracellular retention of these mutants even though they do not hav e polymerogenic properties. These results therefore have important implicat ions for further understanding the fate of mutant alphal-AT molecules, the mechanism of ER retention, and the pathogenesis of liver injury in alphal-A T deficiency.