'Rescue' mutations protect liver from damage in patients with genetic disorder

New research shows how mutations acquired throughout life can protect liver cells from damage caused by an inherited genetic condition. 

Acquired DNA mutations found in the SERPINA1 gene can protect liver cells from damage in patients with alpha-1 antitrypsin deficiency, new research shows. Alpha-1 antitrypsin deficiency (A1AD) is a genetic condition caused by inherited mutations in SERPINA1, that can cause lung and liver disease.

Researchers from the Wellcome Sanger Institute and their collaborators sought to understand if acquired mutations in patients with haemochromatosis, an iron overload disorder, or alpha-1-antitrypsin deficiency offer protection against cell stress.

The study, published today (10 March 2025) in Nature Genetics, provides further understanding about how protective mutations may help inspire therapies in patients with chronic liver disease.

Patients with A1AD are born with faults in a gene called SERPINA1. These faults cause changes to a type of protein called alpha-1 antitrypsin.¹ The changes make alpha-1 antitrypsin proteins stick together and form clumps inside liver cells. The protein clumps damage liver cells, increasing the risk of liver disease and can also lead to chronic obstructed pulmonary disorder (COPD).

The lung symptoms of A1AD can be medically managed and include the use of augmentation therapy², inhaled steroids, antibiotics or intravenous infusions of alpha-1 antitrypsin protein. However, for those with associated liver disease, liver transplantation remains the only treatment option.

In the new study, Sanger Institute researchers and their collaborators explored whether mutations in the liver are disease specific.

As we age, our cells slowly accumulate random mutations in their genes, many of which are harmless. These are known as acquired or somatic mutations. The researchers looked at acquired mutations in those with haemochromatosis and in patients with A1AD to understand if acquired mutations offer protection against cell stress in these conditions.

The team collected liver samples from five patients with haemochromatosis and five with A1AD undergoing transplantation. Samples were collected from patients at Cambridge University Hospitals NHS Foundation Trust.² The researchers used laser capture microdissection on the tissue samples, which involves sectioning the biopsy into a thin slice and using a laser to cut out smaller fractions of roughly 400 cells, which were sequenced to identify somatic mutations.

The researchers found that frequent somatic or acquired mutations in SERPINA1, the gene that encodes for alpha-1 antitrypsin, affect the protein by shortening one end, eliminating the area responsible for the mutated proteins sticking together in A1AD. These protective ‘rescue’ mutations alleviate cell stress, protecting liver cells from damage. The team found no significant mutations in haemochromatosis but note this is likely due to a limited sample size.

Cells with rescue mutations survive better than those without. Over time, these cells grow and divide so more liver cells have the protective mutations, while those with the faulty SERPINA1 gene die out. This is a microscopic demonstration of natural selection.

The study has promising therapeutic implications as currently there is no cure for A1AD associated liver disease beyond liver transplantation. The researchers are now looking to investigate if there is a way of mimicking mutations that can protect people with A1AD from developing the disease.

“Our study reveals a striking example of natural selection at work within our own bodies. Each disease creates its own pressures that drive cells to adapt in different ways. In alpha-1 antitrypsin deficiency, we see a particular ‘rescue’ mutation that helps liver cells survive —but in other conditions, an entirely different set of mutations might emerge. By exploring how cells evolve in response to these varied stressors, we can design new therapies that harness these natural survival strategies not only for A1AD, but potentially for a range of diseases.”

Dr Natalia Brzozowska, first author at the Wellcome Sanger Institute

“We now have a deeper understanding of how A1AD affects the liver cells as, with laser-like focus, we found the area of the protein which can be manipulated in order to prevent damage to the liver cells.  More broadly, the study of acquired mutations allows us to see how diseases affect particular organs and how cells adapt to those diseases. As we look towards the future, we hope to find a way of mimicking these mutations that can protect people with A1AD and other diseases down the line.”

Dr Matthew Hoare, senior author, Associate Professor of Hepatology at the University of Cambridge, based at the Early Cancer Institute, and hepatologist at Addenbrooke’s Hospital in Cambridge

More information

Footnotes

1. Alpha-1 antitrypsin acts as an “off switch” for an enzyme called neutrophil elastase, which helps fight infections in the lungs. Without alpha-1 antitrypsin, neutrophil elastase fails to protect healthy lung tissue.
2. Augmentation therapy is the use of alpha-1 antitrypsin protein derived from the blood of healthy donors to increase the amount of alpha-1 antitrypsin in the lungs of patients with A1AD.
3. The biopsies were obtained in collaboration with The Cambridge Human Research Tissue Bank, supported by the National Institute of Health Research Cambridge Biomedical Research Centre.

Related study

Previously, the Sanger Institute and their collaborators looked at how external factors contribute to mutations acquired throughout a person’s lifetime and the subsequent damage in different tissues. The researchers did not find any cancer-causing mutations in the liver but found those who had either steatotic (fatty) liver disease or alcohol-related liver diseases had mutations in genes which manipulated lipid metabolism. These acquired mutations were found to help hepatocytes (liver cells) better adapt to a toxic environment and survive longer compared to neighbouring cells without these mutations. For more information on this study, the full publication can be found here: Convergent somatic mutations in metabolism genes in chronic liver disease | Nature.

Publication

Brzozowska, et al. (2025) ‘Convergent evolution of somatic escape variants in SERPINA1 in the liver in alpha-1 anti-trypsin deficiency.’ Nature Genetics. DOI: 10.1038/s41588-025-02125-1

Funding

This research is supported by Wellcome, and a full list of acknowledgements can be found in the publication.