A1-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.