Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant messenger RNA (PNPLA3 I148M mRNA)

Patatin-like phospholipase domain-containing protein 3 (PNPLA3), also known as adiponutrin, is an enzyme primarily expressed in hepatocytes and adipocytes that is involved in the hydrolysis of triglycerides and retinyl esters (UniProt P0C615). The I148M variant (rs738409) is a common genetic polymorphism where an isoleucine is substituted for methionine at position 148, which has been identified as a major risk factor for non-alcoholic fatty liver disease (Romeo et al., 2008, Nature Genetics). This mutant protein escapes proteasomal degradation and accumulates on the surface of lipid droplets, where it interferes with lipid mobilization and promotes hepatic steatosis (BasuRay et al., 2017, Nature Communications). Targeting the PNPLA3 148M variant mRNA with RNA-based therapeutics, such as antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs), is a strategy to reduce the levels of the pathogenic protein (Linden et al., 2019, JCI). By lowering the expression of the I148M variant, these therapies aim to decrease liver fat content and prevent the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to more severe stages like cirrhosis or hepatocellular carcinoma (AstraZeneca, 2023). Several clinical-stage candidates, including AZD2693 and GSK4532990, are currently being evaluated for their ability to selectively silence this transcript in patients carrying the risk allele (GSK, 2022).

Other names

Adiponutrin I148M mRNAPNPLA3 rs738409 transcriptPNPLA3-I148M mRNA

Antisense-mediated mRNA degradation via RNase H1 and RNA interference (RNAi) via the RISC complex (Linden et al., 2019, JCI; Alnylam, 2023)