<i>CFHR</i> Gene 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 human <i>CFHR-Factor H</i> gene cluster comprising the complement genes <i>CFHR1</i>, <i>CFHR2</i>, <i>CFHR3</i>, <i>CFHR4</i>, <i>CFHR5</i>, and <i>Factor H</i> 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 <i>CFHR</i> genes, as well as hybrid <i>CFHR-Factor H</i> genes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging: <i>CFHR1</i>, <i>CFHR3</i>, and <i>Factor H</i> gene alterations combined with intact <i>CFHR2</i>, <i>CFHR4</i>, and <i>CFHR5</i> genes are reported in atypical hemolytic uremic syndrome. But alterations in each of the five <i>CFHR</i> genes in the context of an intact <i>Factor H</i> 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.