Serpin family A member 1 (SERPINA1) E342K genomic DNA locus (SERPINA1 E342K locus)

The SERPINA1 E342K genomic DNA locus is the specific chromosomal site within hepatocyte nuclei containing the most common severe mutation responsible for Alpha-1 antitrypsin deficiency (AATD) [UniProt, 2024]. This mutation, known as the Z allele, involves a single nucleotide substitution (G-to-A) that leads to a glutamic acid to lysine change at position 342 of the alpha-1 antitrypsin protein [NIH, 2023]. In hepatocytes, the E342K mutation causes the protein to misfold and polymerize within the endoplasmic reticulum, leading to proteotoxic stress and liver disease [PubMed, 2021]. Because the protein is trapped in the liver, there is a systemic deficiency of circulating alpha-1 antitrypsin, which normally protects lung tissue from neutrophil elastase, resulting in progressive pulmonary emphysema. Modern therapeutic approaches target this genomic locus using gene editing technologies like CRISPR/Cas9 or base editors to permanently correct the mutation [Beam Therapeutics, 2023]. By fixing the DNA sequence in hepatocyte nuclei, these therapies aim to restore the production of functional, secretable alpha-1 antitrypsin while eliminating the production of toxic polymers. Clinical candidates like BEAM-302 utilize adenine base editors to precisely convert the mutant lysine codon back to the wild-type glutamic acid codon [Beam Therapeutics, 2024]. This approach represents a potential one-time curative treatment for both the liver and lung manifestations of the disease.

Other names

Alpha-1 antitrypsin Z mutation locusPiZ allele locusSERPINA1 Glu342Lys locusAATD Z-mutation siteAlpha-1 antitrypsin genomic target

Gene editing (e.g., base editing or CRISPR-mediated correction) to repair the E342K point mutation or knock out the mutant allele to prevent toxic protein accumulation [Beam Therapeutics, 2023; Intellia Therapeutics, 2024].