Alpha-1-antitrypsin (mutant allele) (A1AT, sometimes AAT)

Alpha-1-antitrypsin (A1AT) is a 52 kDa glycoprotein and member of the serpin superfamily, encoded by the SERPINA1 gene on chromosome 14q32; it is synthesized mainly in the liver and circulates in plasma, functioning as the principal inhibitor of neutrophil elastase. Mutations in SERPINA1, particularly the Z allele (Glu342Lys), result in misfolding of the protein, polymerization, and retention in hepatocytes (toxic gain of function in the liver), leading to liver injury, cirrhosis, and increased risk of hepatocellular carcinoma. The parallel plasma deficiency causes loss of elastase inhibition in the lungs (loss of function), predisposing to emphysema and chronic obstructive pulmonary disease. More than 150 pathogenic alleles exist, with variable expressivity and penetrance. Clinical phenotype ranges from asymptomatic to severe lung and liver disease, sometimes in the same individual, depending on genotype, environmental factors (notably smoking), and other molecular modifiers[6][4][2][3]. *Note: For a structured dataset, use "Alpha-1-antitrypsin" as the canonical name and specify the particular mutant allele (e.g., Z, S, Null, or rare variant) when more detail is needed.*

Other names

Mutant A1ATSERPINA1 variantMutant alpha-1-proteinase inhibitorDeficient alpha-1-antitrypsinAAT variantZ allele (most common pathogenic form; also S allele, null alleles, etc.)

Protein replacement restores functional circulating alpha-1-antitrypsin to inhibit neutrophil elastase in the lungs. Investigational therapies may aim to: Enhance degradation of misfolded protein; Block polymerization; Increase correct folding; Silence mutant gene expression.