Using bakersˈ yeast to identify genetic modifiers of alpha‐1 antitrypsin deficiency

Abstract

Around 1 in 2500 individuals in the US have inherited alpha‐1 antitrypsin deficiency (ATD), which manifests as lung and liver disease. The most common cause of ATD is homozygosity for the Z‐variant of AT (ATZ), which accumulates in the endoplasmic reticulum of liver cells as a native polymer. ATZ is inefficiently secreted to the bloodstream, resulting in AT deficiency in the lungs and polymer accumulation in the liver. However, only a subset of ATD patients suffer from liver disease: 10% of patients show liver dysfunction at infancy, and 50% show signs of cirrhosis in adulthood. The factors that predispose this subset of individuals to liver disease are unknown.We have developed a yeast antitrypsin expression system to find candidate genetic factors that affect the risk for ATD‐associated liver disease. This approach takes advantage of the genetic tools available for yeast, as well as the conservation of pathways implicated in ATD‐associated liver disease. Important disease‐associated characteristics of antitrypsin were recapitulated in yeast: the wildtype form was secreted, while mutant ATZ was not. We then screened mutants representing all non‐essential genes in the yeast genome for increased ATZ secretion. Current work is focused on confirming the effect of the candidate genes in a hepatic cell model.Funding from the Alpha‐1 Foundation, Australian Research Council, and the American Australian Association.