Alpha-1-antitrypsin Z variant (A1AT Z (or Z-AAT))

The **Z variant of alpha-1-antitrypsin** is the most common pathological mutation of the alpha-1-antitrypsin (A1AT, encoded by the SERPINA1 gene), arising from a single amino acid substitution at position 342 (glutamic acid to lysine; E342K)[1][4][5][6]. This mutation disrupts the normal folding of the serpin, making it prone to forming ordered polymers in hepatocyte endoplasmic reticulum rather than being efficiently secreted[1][4][5][7]. As a result, individuals homozygous for the Z allele ("PiZZ" genotype) experience a loss of circulating functional A1AT (leading to unchecked neutrophil elastase activity and emphysema) and gain-of-function toxicity from hepatic polymer accumulation (causing liver disease such as neonatal hepatitis, cirrhosis, and hepatocellular carcinoma)[3][4][5][6][7]. The Z variant is responsible for the majority of severe alpha-1-antitrypsin deficiency cases worldwide, representing a classic serpinopathy with both loss- and gain-of-function pathogenic mechanisms[6][4][5][3]. - Alpha-1-antitrypsin Z variant is recognized as a valuable therapeutic target in both pulmonary and hepatic manifestations, with current clinical approaches focusing on intravenous augmentation therapy and experimental strategies exploring pharmacological chaperones to enhance correct folding and secretion[4][5][3].

Other names

Z-α1-antitrypsinZ A1ATZ variant of alpha 1-antitrypsinPiZ

Enzyme replacement/augmentation therapy (restores circulating functional A1AT to inhibit neutrophil elastase in the lungs); Pharmacological chaperones (promote proper folding and secretion, prevent polymerization in hepatocytes)