eprintid: 10093619 rev_number: 21 eprint_status: archive userid: 608 dir: disk0/10/09/36/19 datestamp: 2020-03-18 10:45:29 lastmod: 2021-06-16 06:10:04 status_changed: 2020-08-13 17:53:16 type: article metadata_visibility: show creators_name: Perkins, S title: Genetic and protein structural evaluation of atypical haemolytic uremic syndrome and C3 glomerulopathy ispublished: pub divisions: UCL divisions: A01 divisions: B02 divisions: C08 divisions: D09 divisions: G03 keywords: Allele frequencyAtypical hemolytic uremic syndromeC3 glomerulopathyComplement alternative pathwayRare variant database note: This version is the author accepted manuscript. For information on re-use, please refer to the publisherÃs terms and conditions. abstract: Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with loss of regulation of the alternative pathway of complement and its resulting overactivation. As rare diseases, genetic variants leading to aHUS and C3G were previously analysed in relatively low patient numbers. To improve this analysis, data were pooled from six centres. Totals of 610 rare variants for aHUS and 82 for C3G were presented in an interactive database for 13 genes. Using allele frequency comparisons with the Exome Aggregation Consortium as a reference genome, the patients with aHUS showed significantly more protein-altering ultrarare variants (allele frequency <0.01%) in five genes CFH, CFI, CD46, C3, and DGKE. In patients with C3G, the corresponding association was only found for C3 and CFH. Protein structure analyses of these five proteins showed distinct differences in the positioning of these variants in C3 and FH. For aHUS, variants were clustered at the C-terminus of FH and implicated changes in the binding of FH to host cell surfaces. For C3G, variants were clustered at the N-terminal C3b binding site of FH and implicated changes in the fluid-phase regulation of C3b. We discuss the utility of the Web database as a patient resource for clinicians. date: 2020-03 date_type: published official_url: https://doi.org/10.1053/j.ackd.2020.03.002 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1772604 doi: 10.1053/j.ackd.2020.03.002 lyricists_name: Perkins, Stephen lyricists_id: SJPER24 actors_name: Perkins, Stephen actors_id: SJPER24 actors_role: owner full_text_status: public publication: Advances in Chronic Kidney Disease volume: 27 number: 2 pagerange: 120-127 issn: 1548-5595 citation: Perkins, S; (2020) Genetic and protein structural evaluation of atypical haemolytic uremic syndrome and C3 glomerulopathy. Advances in Chronic Kidney Disease , 27 (2) pp. 120-127. 10.1053/j.ackd.2020.03.002 <https://doi.org/10.1053/j.ackd.2020.03.002>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10093619/3/Perkins_Genetic%20and%20protein%20structural%20evaluation%20of%20atypical%20haemolytic%20uremic%20syndrome%20and%20C3%20glomerulopathy_AAM.pdf