SPECIAL SEMINAR - Stefan MARCINIAK : Professor University of CAMBRIDGE and Pulmonologist at Cambridge University Hospitals and Royal Papworth Hospital

Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsindeficiency

Pr. Stefan MARCINIAK

Professor of Respiratory Science at the University of Cambridge

Pulmonologist at Cambridge University Hospitals and Royal Papworth Hospital

Director of the MB/PhD program Cambridge

Director of the NHS England Rare Disease Collaborative Network (RDCN) in Familial Pneumothorax and co-leader of the LifeArc Rare Respiratory Disease Centre

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.