Stefan Marciniak, PhD - "Somatic escape variants of SERPINA1 in ⍺1-antitrypsin deficiency"
- When Sep 30, 2025 from 12:00 PM to 01:15 PM (Europe/Berlin / UTC200)
- Where Tigem Auditorium Angelo Maramai
- Contact Name Nicola Brunetti
- Contact Phone 08119230659
-
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- https://www.tigem.it/newsroom/seminars/stefan-marciniak-phd-protein-folding-pathways-across-physiology-and-therapy201d
- Stefan Marciniak, PhD - "Somatic escape variants of SERPINA1 in ⍺1-antitrypsin deficiency"
- 2025-09-30T12:00:00+02:00
- 2025-09-30T13:15:00+02:00
Stefan Marciniak, PhD
Professor of Respiratory Science
Cambridge Institute for Medical Research
Cambridge, UK
&
Royal Papworth Hospital
Trumpington, UK
Short CV
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
Professor of Respiratory Science
Cambridge Institute for Medical Research
Cambridge, UK
&
Royal Papworth Hospital
Trumpington, UK
Short CV
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