Alpha-1 antitrypsin (Z mutant) (PiZ)

Alpha-1 antitrypsin (AAT), encoded by the SERPINA1 gene, is a member of the serpin superfamily and functions primarily as a serine protease inhibitor that protects lung tissue from degradation by neutrophil elastase (MedlinePlus, 2021). The Z mutant (Glu342Lys) is the most common severe variant associated with alpha-1 antitrypsin deficiency (AATD), characterized by protein misfolding and the formation of ordered polymers within the endoplasmic reticulum of hepatocytes (NIH, 2021). This accumulation leads to a toxic gain-of-function that causes liver injury, including cirrhosis and hepatocellular carcinoma, while the resulting deficiency of circulating AAT leads to a loss-of-function in the lungs, predisposing patients to early-onset emphysema (NIH, 2007). Therapeutic approaches targeting the Z mutant include RNA interference (RNAi) to silence the production of the toxic protein in the liver and small molecule correctors designed to stabilize the protein's conformation and promote its secretion (Patsnap, 2025; Z Factor, 2020). Additionally, intravenous augmentation therapy is used to restore the protease-antiprotease balance in the lungs by providing exogenous AAT (NIH, 2026). Monitoring of these therapies often involves measuring serum AAT levels, Z-AAT polymer concentrations, and liver enzymes to assess efficacy and safety (NIH, 2024).

Other names

Alpha-1 antitrypsin Z variantSERPINA1 Z mutantPiZGlu342Lys mutantE342K mutantAlpha-1 antitrypsin (AAT) Z variant

RNA interference (RNAi) to silence hepatic mRNA and reduce toxic protein accumulation; small molecule correctors to stabilize protein folding and promote secretion; augmentation therapy to restore protease-antiprotease balance in the lungs.