SERPINA1

About SERPINA1

SERPINA1 on chromosome 14q32.13 encodes alpha 1 antitrypsin, a serine protease inhibitor made mainly by the liver that circulates in the blood and protects tissues, especially the lungs, from neutrophil elastase. Variants are designated by letters according to their behavior on electrophoresis, the protease inhibitor or Pi system, with M as the normal allele. The Z allele, a Glu342Lys substitution, causes the protein to misfold and polymerize in liver cells, so little reaches the bloodstream, and the S allele causes milder deficiency. Alpha 1 antitrypsin deficiency was described in 1963 by Carl Bertil Laurell and Sten Eriksson in Sweden. People with the PiZZ genotype, which is most common in people of European ancestry, are at risk of early onset emphysema, often predominating in the lower lobes, because unopposed elastase destroys alveolar walls, and smoking dramatically accelerates this damage. Accumulation of polymerized protein in the liver can cause neonatal jaundice, hepatitis, cirrhosis, and liver cancer. The liver and lung diseases thus have distinct mechanisms, a toxic gain of function in the liver and loss of function in the lung. Treatment options include intravenous augmentation therapy with purified alpha 1 antitrypsin, lung or liver transplantation, and RNA interference drugs that silence production of the Z protein, which are in clinical trials.