Alpha 1-antitrypsin (alpha-1AT) deficiency is a common inherited disease associated with emphysema in adults and liver disease in children. The goal of our laboratory is to characterize the molecular causes of alpha- 1AT deficiency and explore methods of treatment. Our basic studies have focused on determining the molecular nature of alpha-1AT deficiency variants by utilizing natural errors in the alpha-1AT gene and protein to understand how alpha-1AT is made, transported and functions. We have demonstrated that the major mechanism for disposal of the most common abnormal alpha-1AT variant, Z alpha-1AT, is via intracellular degradation in the rough endoplasmic (RER). Degradation of Z and normal M alpha-1AT is the result of a delay in movement from the RER to the next intracellular processing compartment. When drugs are used to inhibit degradation of alpha-1AT, movement to the Golgi and secretion of the Z protein occurs in amounts comparable to the normal alpha-1AT. In addition to our basic research, we are the largest study center involved in the National alpha-1AT Deficiency Registry, which is in its last year of a 6 year study. The most important new observations to emerge from this multi-center study include: 1) reactive airways is a marker for rapid decline in lung function; 2) non-transplanted individuals survive longer than those who are transplanted; and 3) among individuals with lung disease, ex-smokers have the same rate of decline in lung function as individuals who never smoked.
