CFHRGene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

Abstract

Sequence and copy number variations in the humanCFHR–Factor Hgene cluster comprising the complement genesCFHR1,CFHR2,CFHR3,CFHR4,CFHR5, andFactor Hare 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 mutantCFHRgenes, as well as hybridCFHR–Factor Hgenes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging:CFHR1,CFHR3, andFactor Hgene alterations combined with intactCFHR2,CFHR4, andCFHR5genes are reported in atypical hemolytic uremic syndrome. But alterations in each of the fiveCFHRgenes in the context of an intactFactor Hgene 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.