Serpin family A member 1 Z-allele messenger RNA (SERPINA1-Z mRNA) (SERPINA1-Z mRNA)

Serpin family A member 1 (SERPINA1) Z-allele messenger RNA is the transcript produced from the mutated SERPINA1 gene, specifically carrying the G-to-A point mutation that results in a glutamic acid to lysine substitution at position 342 (Glu342Lys) [UniProt P01009]. This mutation characterizes the Z-allele, the most common cause of severe Alpha-1 Antitrypsin Deficiency (AATD). The resulting Z-alpha-1 antitrypsin (Z-AAT) protein is prone to misfolding and polymerization within the endoplasmic reticulum of hepatocytes, preventing its secretion into the circulation [Strnad et al., 2020, NEJM]. This leads to a dual pathology: a toxic gain-of-function in the liver due to intracellular polymer accumulation causing cirrhosis, and a loss-of-function in the lungs due to the lack of circulating protease inhibitor, leading to emphysema. Therapeutic interventions targeting the Z-allele mRNA, such as siRNAs like fazirsiran and RNA editing tools like WVE-006, aim to reduce the production of the toxic protein at the source [Turner et al., 2024, Lancet; Wave Life Sciences, 2023]. By silencing or correcting this specific mRNA, these treatments seek to alleviate liver proteotoxicity and prevent the progression of liver disease in affected individuals.

Other names

AAT-Z mRNAAlpha-1 antitrypsin Z-mutation mRNAPI*Z mRNA transcriptSERPINA1 Glu342Lys mRNA

RNA interference (RNAi) mediated degradation, RNA editing, and antisense-mediated translational inhibition.