Serpin family A member 1 (SERPINA1) gene (SERPINA1)

The Serpin family A member 1 (SERPINA1) gene, located on chromosome 14q32.13, encodes Alpha-1 antitrypsin (A1AT), a major circulating serine protease inhibitor primarily synthesized in hepatocytes (UniProt P01009). The presence of pathogenic alleles, most notably the PiZ variant (Glu342Lys), leads to the production of misfolded A1AT proteins that polymerize within the endoplasmic reticulum of liver cells (PubMed: 33106611). This accumulation causes a toxic gain-of-function resulting in liver inflammation, cirrhosis, and an increased risk of hepatocellular carcinoma, while the lack of secreted A1AT leads to a loss-of-function in the lungs, predisposing patients to early-onset emphysema (NIH: Genetics Home Reference). Therapeutic strategies targeting the SERPINA1 pathogenic allele in hepatocyte nuclear DNA utilize advanced genetic technologies such as CRISPR/Cas9 and base editing to permanently modify the genomic sequence. These interventions aim to either silence the production of the proteotoxic Z-A1AT protein or, more ideally, correct the point mutation to restore the synthesis and secretion of functional, wild-type A1AT (Beam Therapeutics; Intellia Therapeutics). By addressing the root genetic cause within the nucleus, these therapies represent a potential one-time curative approach for both the liver and lung manifestations of Alpha-1 antitrypsin deficiency.

Other names

Alpha-1 antitrypsin geneA1AT genePIAATSerpin A1 genePiZ allele

Direct genomic modification via base editing to correct point mutations or gene insertion/knockout to eliminate toxic protein production and restore functional protein levels.