A rare inherited variant in the MET gene may cause steatotic liver disease (SLD) in some patients, according to a study published in Hepatology. The findings suggest that, in rare cases, a single genetic alteration may drive disease development rather than the combination of metabolic and environmental factors typically associated with the condition.
Metabolic dysfunction–associated steatotic liver disease (MASLD) affects about one-third of adults worldwide and can progress to metabolic dysfunction–associated steatohepatitis, cirrhosis, and hepatocellular carcinoma. The disease is usually associated with metabolic risk factors such as obesity, diabetes, or dyslipidemia, and previously identified genetic contributions have generally involved common variants rather than single-gene causes.
In this study, by the Mayo Clinic, researchers identified a previously unreported germline variant in the MET gene in a family with metabolic dysfunction–associated steatohepatitis who lacked typical metabolic risk factors. Exome sequencing detected a mutation in the MET kinase domain.
Functional analyses – including protein modeling, molecular dynamics simulations, and cell-based assays – were performed to evaluate the effect of the variant on cellular signaling. The results suggested that disruption of MET signaling can alter pathways involved in hepatocyte lipid metabolism, contributing to hepatic fat accumulation and inflammation.
To assess whether similar variants might occur in a broader population, investigators analyzed exome sequencing data from 3,904 individuals with steatotic liver disease. Rare predicted deleterious MET variants were identified in 45 patients (1.1 percent). Among these, eight individuals (17.7 percent) had variants located in the same kinase domain region as the familial mutation, with functional characteristics similar to the original variant.
The discovery originated from genomic investigation of a woman and her father who both developed steatohepatitis without diabetes or high cholesterol. Researchers sequenced more than 20,000 genes to identify a potential cause and found a single nucleotide change in MET that altered the encoded protein and disrupted signaling involved in hepatic fat metabolism.
The authors describe this as the first reported germline, nonmalignant MET-driven monogenic form of steatotic liver disease and note that additional studies are needed to determine how detection of pathogenic MET variants may inform diagnostic evaluation and risk assessment in liver disease.
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