Alpha-1 antitrypsin (SERPINA1) Z-mutant gene (SERPINA1-Z)

The mutant Z-AAT gene, a specific variant of the SERPINA1 gene characterized by a Glu342Lys mutation, is the primary driver of liver pathology in Alpha-1 Antitrypsin Deficiency (AATD). In hepatocytes, this mutation causes the alpha-1 antitrypsin protein to misfold and form insoluble polymers that accumulate within the endoplasmic reticulum (UniProt Consortium, 2023). This intrahepatic accumulation leads to a toxic gain-of-function, resulting in chronic cellular stress, inflammation, and an increased risk of liver cirrhosis and hepatocellular carcinoma (Turner et al., 2024). Conversely, the failure to secrete functional AAT into the bloodstream leads to a loss-of-function in the lungs, where the lack of protease inhibition results in emphysema. Modern therapeutic strategies focus on silencing the mutant gene using RNA interference (RNAi) or antisense oligonucleotides (ASOs) to stop the production of the toxic protein at its source. By reducing the hepatic burden of Z-AAT polymers, these treatments aim to allow the liver to recover and prevent progression to end-stage liver disease (Strnad et al., 2020). Clinical candidates like Fazirsiran have demonstrated the ability to significantly lower intrahepatic Z-AAT levels and improve histological markers of liver health in affected patients.

Other names

Alpha-1 antitrypsin Z-allelePiZ alleleSERPINA1*ZMutant alpha-1 antitrypsin geneZ-AATZ-type alpha-1 antitrypsin

RNA interference (RNAi) mediated silencing of the mutant SERPINA1 mRNA to prevent the synthesis and subsequent aggregation of toxic Z-AAT protein in hepatocytes (Strnad et al., 2020).