ArticleNature genetics2025
Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency.
Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Understanding the somatic evolution of metabolic traits.Nature metabolism · 2026Article
- Germline mutations and somatic mosaicism in steatotic liver diseases and related liver carcinogenesis.Nature reviews. Gastroenterology & hepatology · 2026Review
- Review
- How somatic evolution affects health.Nature ecology & evolution · 2026Article
- Challenges in the diagnosis and treatment of genetic cholestasis in adults.JHEP reports : innovation in hepatology · 2026Review
- Molecular insights on the mechanism of α1-antitrypsin condensate formation and maturation.PLoS computational biology · 2025Article
- The interplay between germline and somatic variants in alpha-1 anti-trypsin deficiency liver disease.Nature genetics · 2025Article
- Alpha-1 Antitrypsin Deficiency Alleles in Non-Cirrhotic Hepatocellular Carcinoma: Insights from a Multicenter French Cohort.Journal of clinical and experimental hepatologyArticle
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12 authors.
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Abstract
Somatic variants accumulate in non-malignant tissues with age. Functional variants, leading to clonal advantage of hepatocytes, accumulate in the liver of patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing etiologies is unknown. We analyzed liver somatic variants in patients with genetic CLD from alpha-1 antitrypsin (A1AT) deficiency or hemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered at the carboxyl terminus of A1AT, leading to truncation. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting that functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.
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