Prof Stefan Marciniak; Cambridge Institute for Medical Research, University of Cambridge
I studied medicine at the University of Cambridge as part of its MB/PhD program. After training in respiratory medicine in Cambridge, London and Edinburgh, I undertook post-doctoral research in New York University for three years and then again in Cambridge. In 2012,I established my lab in the Cambridge Institute for Medical Research (CIMR) to study diseases caused by abnormal protein folding, including alpha1-antitryspin deficiency. In 2016, I was elected the Professor of Respiratory Science at the University of Cambridge. In Cambridge, I direct the MB/PhD program, while nationally I direct the NHS England Rare Disease Collaborative Network (RDCN) in Familial Pneumothorax.
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 aetiologies is unknown. We analyzed liver somatic variants in patients with genetic CLD from alpha-1 antitrypsin (A1AT) deficiency or haemochromatosis. 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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