Alpha1-antitrypsin (A1AT) deficiency
Alpha1-antitrypsin (A1AT) deficiency is a relatively rare genetic disorder that causes affected individuals to have a predisposition to developing early signs of chronic obstructive pulmonary disorder (COPD), non-alcoholic cirrhosis of the liver, and in some cases, a skin disease called panniculitis. The most common cause of mortality in individuals with A1AT deficiency is emphysema, with liver disease following closely behind.
The disorder is due to defective alleles of the SERPINA1 gene, which encodes the A1AT protein. The protein’s normal physiological function is to act as a check on neutrophil elastase, an enzyme secreted by neutrophils in response to lung inflammation. The normal allele is denoted M. There are two mutant disease-causing alleles that are autosomal codominant: S and Z. Heterozygotes (MS and MZ) have a somewhat elevated risk of COPD, especially if they smoke; homozygous ZZ individuals have the most severe phenotype, with an extremely high risk of developing emphysema.
In many individuals with severe cases of A1AT deficiency (the ZZ genotype), intracellular accumulations in the liver are usually noted upon biopsy. What might be the cause of this phenomenon? What are the accumulations of, where in the cell would you expect to find them and why, and where do they come from? Hint… think about the normal physiological processes that occur within a cell, and how the defective A1AT protein arising from the Z allele might interfere with these processes.
