Alpha-1 antitrypsin (Z variant) (Z-AAT)

Alpha-1 antitrypsin (Z variant), or Z-AAT, is a mutant form of the SERPINA1 protein characterized by a glutamic acid to lysine substitution at position 342 (UniProt P01009). This specific mutation causes the protein to misfold and form large, insoluble polymers that aggregate within the endoplasmic reticulum of hepatocytes, the primary site of its synthesis (NIH, 2023). The accumulation of these polymers causes proteotoxic stress, leading to liver inflammation, fibrosis, and potentially cirrhosis or hepatocellular carcinoma (PubMed: 32633674). Furthermore, the failure of Z-AAT to be secreted into the circulation results in a severe deficiency of the protein in the lungs, where its primary role is to inhibit neutrophil elastase (StatPearls, 2023). Without this inhibition, lung tissue undergoes progressive proteolytic destruction, resulting in early-onset emphysema and chronic obstructive pulmonary disease. Modern drug development targets Z-AAT through two primary modalities: RNA interference (RNAi) to silence the production of the mutant protein in the liver and small molecule correctors designed to stabilize the protein's monomeric form and facilitate its secretion (ClinicalTrials.gov). These therapies aim to alleviate the liver burden while potentially restoring some level of systemic protease protection.

Other names

PiZSERPINA1 (Glu342Lys)Z-type alpha-1 antitrypsinAlpha-1-proteinase inhibitor (Z variant)

RNA interference (RNAi) to silence hepatic production of the mutant protein; small molecule correctors to prevent misfolding and polymerization.