Serpin family A member 1 (SERPINA1) gene E342K mutation locus (SERPINA1 E342K)

The SERPINA1 gene E342K mutant locus is the specific genomic site responsible for the PiZ variant of alpha-1 antitrypsin deficiency (AATD), characterized by a G-to-A transition (UniProt: P01009). This mutation leads to the substitution of glutamic acid with lysine at position 342, causing the alpha-1 antitrypsin (AAT) protein to misfold and polymerize within the endoplasmic reticulum of hepatocytes (PubMed: 32661353). The resulting intracellular accumulation causes chronic liver injury, cirrhosis, and increases the risk of hepatocellular carcinoma, while the lack of circulating AAT leads to lung tissue degradation and emphysema (NIH: NBK1519). As a therapeutic target, this locus is the focus of advanced genetic medicines, including base editors like BEAM-302, which aim to precisely correct the mutation back to the wild-type sequence (Beam Therapeutics, 2023). By targeting the genomic DNA in hepatocytes, these therapies seek to eliminate the production of toxic mutant polymers and restore the secretion of functional, protective AAT into the systemic circulation. This approach addresses both the hepatic and pulmonary manifestations of the disease at the genetic source.

Other names

Alpha-1 antitrypsin PiZ mutationAATD Z-alleleSERPINA1 PiZ locusGlu342Lys mutation locusrs28929474

Correction of the E342K point mutation via base editing or gene replacement to restore wild-type SERPINA1 expression and reduce toxic protein aggregation.