CFHR Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy
Peter F. Zipfel, Thorsten Wiech, Emma Diletta Stea, Christine Skerka
Abstract
Significance Statement The human CFHR–Factor H gene cluster encodes the five FHR proteins that are emerging complement and immune modulators and the two complement regulators Factor H and FHL1. Genetic and chromosomal alterations in this cluster are associated with the human kidney diseases atypical hemolytic uremic syndrome and C3 glomerulopathy. Various genetic alterations result in the expression of mutant and altered FHR proteins, or FHR::Factor H and Factor H::FHR hybrid proteins. The modified FHR proteins together with an altered FHR and Factor H plasma repertoire, which often modify complement action in the fluid phase and cause morphologic alteration in the glomerulus, provide important views on FHR protein function in the kidney. Sequence and copy number variations in the human CFHR–Factor H gene cluster comprising the complement genes CFHR1 , CFHR2 , CFHR3 , CFHR4 , CFHR5 , and Factor H are linked to the human kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy. Distinct genetic and chromosomal alterations, deletions, or duplications generate hybrid or mutant CFHR genes, as well as hybrid CFHR–Factor H genes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging: CFHR1 , CFHR3 , and Factor H gene alterations combined with intact CFHR2 , CFHR4 , and CFHR5 genes are reported in atypical hemolytic uremic syndrome. But alterations in each of the five CFHR genes in the context of an intact Factor H gene are described in C3 glomerulopathy. These genetic modifications influence complement function and the interplay of the five FHR proteins with each other and with Factor H. Understanding how mutant or hybrid FHR proteins, Factor H::FHR hybrid proteins, and altered Factor H, FHR plasma profiles cause pathology is of high interest for diagnosis and therapy.