The V444A polymorphism is a significant risk factor for ICP in this population. N591S is a recurrent mutation however, the mechanism may be independent of protein stability or function. The molecular basis of V444A and N591S was not apparent from the Sav1866 structure.Ĭonclusions: Heterozygosity for the common ABCB11 mutations accounts for 1% of European ICP cases these two mutants probably reduce the folding efficiency of BSEP. Structural analyses suggest that E297G and D482G destabilise the protein fold of BSEP. In addition, CC homozygotes were more likely to have ICP than TT homozygotes: OR 2.8 (95% CI 1.7 to 4.4 p<0.0001). The V444A polymorphism was associated with ICP (allelic analysis for C vs T: OR 1.7 (95% CI 1.4 to 2.1, p<0.001)). N591S was present in two patients D676Y and G855R were not observed. Results: E297G was observed four times and D482G once.
The molecular basis for the observed phenotypes was investigated in silico by analysing the equivalent residues in the structure of the homologous bacterial transporter Sav1866. PCR primers were used to amplify and sequence patient and control DNA. Methods: ABCB11 variation in ICP was investigated by screening for five mutant alleles (E297G, D482G, N591S, D676Y and G855R) and the V444A polymorphism (c.1331T>C, rs2287622) in two ICP cohorts (n = 333 UK, n = 158 continental Europe), and controls (n = 261) for V444A. The disclosed anti-SARS-CoV-2 antibodies constitute a novel therapeutic strategy in protection from SARS-CoV-2 infections. ABCB11 encodes the bile salt export pump (BSEP) mutations cause a spectrum of cholestatic disease, and are implicated in the aetiology of ICP. This disclosure provides novel broadly neutralizing anti-SARS-CoV-2 antibodies or antigen-binding fragments thereof. Professor C Williamson, Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK .ukīackground: Intrahepatic cholestasis of pregnancy (ICP) has a complex aetiology with a significant genetic component.10 MRC Clinical Sciences Centre, Imperial College London, London, UK.At present not much is known about its biological actions, and comparative studies of SPX in nonmammalian species are still lacking. 9 Institute of Child Health, University College London, London, UK Spexin (SPX) is a neuropeptide identified recently by bioinformatic approach.8 London School of Hygiene and Tropical Medicine, University of London, London, UK.7 Karolinska Institutet, Department of Medicine at Karolinska University Hospital Huddinge, Stockholm, Sweden.6 Department of Obstetrics and Gynecology, Sahlgrenska University Hospital/East, Göteborg, Sweden.5 Department of Gastroenterology, Hepatology and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.4 Department of Medicine I, Saarland University Hospital, Homburg, Germany.3 Department of Liver Studies and Transplantation, King’s College London School of Medicine, London, UK.
2 Laboratory for Metabolic and Endocrine Diseases, UMC Utrecht, Utrecht, The Netherlands.1 Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, London, UK.