%O This version is the author accepted manuscript. For information on re-use, please refer to the publisherís terms and conditions.
%X 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.
%L discovery10093619
%K Allele frequencyAtypical hemolytic uremic syndromeC3 glomerulopathyComplement alternative pathwayRare variant database
%J Advances in Chronic Kidney Disease
%D 2020
%P 120-127
%N 2
%V 27
%A S Perkins
%T Genetic and protein structural evaluation of atypical haemolytic uremic syndrome and C3 glomerulopathy