Autosomal recessive

Leads to chronic pulmonary obstruction and cirrhosis of the liver

alpha-1-antitrypsin gene is on chromosome 14. It has 75 genetic variants. The Z allele (E342K) is common.

Z mutant aggregates in the endoplasmic reticulum

alpha-1-antitrypsin is the most common cause of liver disease among children. Symptoms include jaundice, swelling of the abdomen and legs, poor appetite, and 20-fold increased risk of developing emphysema and cirrhosis.

Smoking oxidizes methionine in the protein active site and aggravates the condition.

There are three variants of the alpha-1-antitrypsin allele. The M variant, the S variant, and the Z variant.

M variant is normal.

S variant is a GAA to GTA mutation in exon 3, val264glu. This results in the production of an inhibitor with decreased stability.

Z variant is GAG to AAG mutation in exon 5, asp342lys. This change has been shown to cause decreased processing and secretion of the abnormal alpha-1-antitrypsin in the liver, a major source of its biosynthesis, as well as in mononuclear macrophages.

Alpha-1-antitrypsin normally inhibits elastase released during phagocytosis by neutrophils present in alveoli of the lungs.

A deficiency in alpha-1-antitrypsin permits neutrophil elastase to destroy lung.