As we age, somatic mutations build up in our tissues, often undetected. But in the liver, these genetic changes can play a surprising role in chronic liver disease (CLD). A study published in Nature Genetics uncovers how somatic mutations provide a clonal advantage to hepatocytes, reshaping the liver’s genetic landscape in response to specific diseases.
Researchers from the Wellcome Trust Sanger Institute and the University of Cambridge delved into the livers of patients with genetic CLD caused by alpha-1 antitrypsin (A1AT) deficiency and hemochromatosis, revealing a striking discovery: mutations in the SERPINA1 gene—responsible for A1AT production—undergo convergent evolution in A1AT deficiency. These mutations cluster in a specific region of the SERPINA1 gene, leading to protein truncation that mitigates cellular stress and provides clonal survival advantages, revealing potential therapeutic mechanisms for CLDs like A1AT deficiency.
Evolving genetic insights on chronic liver disease
A change is occurring in the origins of CLD, which is a significant cause of death globally (1 in 25 deaths worldwide). Once dominated by viral hepatitis, the landscape is now shaped by the global rise in obesity and type 2 diabetes, driving an epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD). Yet, a significant portion of CLD cases stems from inherited genetic disorders like hemochromatosis and A1AT deficiency, each with unique mechanisms of liver damage. Hemochromatosis, prevalent in northern Europe, arises from mutations in genes regulating iron metabolism, leading to harmful iron deposits in liver cells. Meanwhile, A1AT deficiency, linked to the Z-variant of the SERPINA1 gene, triggers protein polymerization in liver cells, causing endoplasmic reticulum stress and cell death. For patients with progressive A1AT deficiency, liver transplantation remains the only treatment option.
Recent discoveries highlight how somatic mutations—spontaneous genetic changes in liver cells—may help the organ adapt to disease-specific stress. Research shows that diseases like MASLD and alcohol-related liver disease select for mutations in metabolism-related genes like FOXO1, CIDEB, and GPAM, promoting clonal expansion of hepatocytes by altering carbohydrate and lipid metabolism. These adaptive mutations suggest that distinct CLD types create unique microenvironments that shape genetic evolution in the liver. Intriguingly, protective somatic mutations could inspire new treatments. By mimicking these naturally advantageous changes, researchers might uncover therapeutic strategies for liver diseases where options remain limited, offering hope for millions battling these deadly conditions.
Somatic variants in SERPINA1
Researchers used cutting-edge genomic tools, including whole-genome sequencing (WGS) and whole-exome sequencing (WES), to investigate liver tissue from ten transplant patients. Five had PiZZ A1AT deficiency (a severe form characterized by homozygous Z-variant alleles), and five had hemochromatosis. By applying laser-capture microdissection, the team examined 306 liver samples with high-resolution genetic analysis, achieving robust data coverage.
The study unveiled a remarkable phenomenon: the convergent evolution of somatic mutations in SERPINA1 in A1AT-deficient patients, which showed frequent and independent mutations in various liver cell clones. Notably, the mutations clustered in the gene’s C-terminal region, which plays a pivotal role in the protein’s folding and polymerization. In one striking case, a single liver sample harbored 11 independent clones of mutated SERPINA1 within a tiny tissue area. Most mutations were heterozygous, suggesting they offer a survival advantage to affected hepatocytes without fully restoring normal gene function.
The study further explored how these mutations influence protein behavior. A1AT deficiency is marked by the misfolding and polymerization of the protein, leading to toxic accumulation within the endoplasmic reticulum (ER) of liver cells. Researchers modeled two specific truncation variants, Z-K367* and Z-E387*, in cell cultures. These variants disrupted the usual polymerization process, reducing the formation of harmful A1AT polymers while also altering ER dynamics. Interestingly, while these truncated proteins showed a reduced propensity for polymerization, they did not fully restore normal protein secretion. Instead, they underwent degradation via the proteasome, a cellular system for clearing defective proteins. This degradation explains the lower levels of these variants in liver cells.
A new chapter in liver disease research
Emerging therapies for A1AT deficiency, such as liver-directed RNA interference, have demonstrated potential in suppressing Z-A1AT expression in mouse models and early human trials. Alternatively, targeting or deleting the A1AT protein’s C-terminal region could offer a novel approach to preventing harmful polymer formation. While these strategies may enhance hepatocyte survival and slow liver disease progression, they do not restore normal A1AT secretion or serum levels, leaving lung disease associated with A1AT deficiency unaddressed.
Scientists can design interventions that mimic these mutations’ effects by identifying how specific mutations in SERPINA1 alter protein behavior. Such strategies could reduce polymer accumulation, alleviate ER stress, and slow the progression of liver damage in A1AT deficiency. Moreover, the discovery of dominant-negative effects in some truncation variants suggests that these mutations could actively counteract harmful polymerization, paving the way for targeted genetic or pharmacological therapies.
