Natalia Brzozowska

Oops - called it a preprint when it’s actually a paper in Nature Genetics! Excited to see it out in the world!

Huge thanks to patients & families, Peter Campbell and @matthoare20.bsky.social who led this work, @profmarciniak.bsky.social and team for fantastic collaboration, @imartincorena.bsky.social and team for insights and support, @timcoorens.bsky.social, Daniel Leongamornlert, and many others! [12/12]

Overall, our findings reveal the liver's remarkable ability to evolve in response to genetic and acquired disease. Understanding these natural survival strategies could inspire new therapies — not just for A1AD, but potentially many other diseases. [11/12]

Additional experiments suggested these shortened proteins didn't just reduce aggregates by losing their own polymerisation capability. Instead, they may actively interfere with aggregation of the pathogenic allele. This 'dominant-negative' effect could offer new therapeutic strategies. [10/12]

We further studied these variants in the lab and discovered they were rapidly cleared by the cell’s proteasome, explaining their lower levels compared to the disease-causing form. [9/12]

Returning to human liver tissue, we confirmed this beneficial effect: shortened protein variants clearly reduced aggregate formation, demonstrating a natural 'rescue' mechanism in patients. [8/12]

We collaborated with @profmarciniak.bsky.social lab to validate these mutations in cellular models. The shortened protein forms indeed accumulated less, reducing disruption in the endoplasmic reticulum (ER). [7/12]

Remarkably, mutations frequently targeted SERPINA1 itself — specifically its last exon. We hypothesised that those C-terminal mutations shortened the Z-A1AT protein, preventing harmful aggregation and allowing mutated cells to dominate liver tissue. [6/12]

We analysed 5 liver samples from transplanted A1AT deficiency patients using laser-capture microdissection. We performed DNA sequencing on those tiny microbiopsies to map somatic mutations across liver tissue sections. [5/12]

Alpha-1 antitrypsin (A1AT) deficiency is caused by a genetic mutation ('Z') in SERPINA1, affecting the A1AT protein. Normally released into the bloodstream to protect the lungs, the mutant form aggregates inside liver cells, causing inflammation, cirrhosis, and eventually liver failure. [4/12]

Genes targeted by driver mutations vary by cell type and environment, influencing organ-specific patterns. Previously, we saw mutations in lipid metabolism genes dominate liver disorders linked to metabolic disease. Could this differ in other liver disorders? [3/12]

Somatic mutations are changes to DNA that accumulate in our cells as we age. While many are neutral, some ('driver mutations') give cells an adaptive advantage, causing them to grow into larger clones. By middle age, many tissues become patchworks of these clones. [2/12]

Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency - Nature Genetics The expansion of clones with distinct SERPINA1 somatic mutants in the livers of alpha-1 antitrypsin deficiency (A1AT) patients is consistent with convergent evolution. These variants interfere with th...

Excited to share our new preprint demonstrating somatic rescue mutations in a genetic liver disease! [1/12]

www.nature.com/articles/s41...