CFHR 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 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.

CFHR5 Genetic Variations and Serum Levels in Patients with Immune-Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy

“…In an other perspective, interaction between FHR proteins and the extracellular matrix components can also modify the regulator activity of FHR proteins. The interactions between FHR-5 protein and the surface components such as glycosaminoglycans may also play a role in complement dysregulation (25). As C3G is considered as a polygenic disease, variations in CFHR5 are supposed to play a disease-modifying role in C3G predisposition and disease development.…”

“…This homology raises the possibility that FHRs can compete with FH for the binding of C3b (21,22). Moreover, FHR-5 can bind to heparin, Creactive protein, pentraxin-3 and the extracellular matrix (21,23) and it can also inhibit the C3-and C5convertases based on previous studies (21,24,25)). FHR-5 was described as a pathogenic factor in a subtype of C3G (26,27).…”

“…(35) Probably not only the FHR proteins's plasma levels, but modi ed FHR and FH plasma repertoire may also affect the complement regulation on the endothelial surface or in the uid-phase resulting in cell injury. Interactions with glycosaminoglycans can also affect the functions of the above mentioned proteins (25). However, detailed genetic and functional analysis of CFHR5 along with the parallel measurement of serum levels of the protein have not been performed in a large number of IC-MPGN and C3G patients.…”

Identification of C3GN Presenting in a Proband with Family History of Alport Syndrome

“…CFHR5 colocalizes with complement-containing glomerular immune deposits in a variety of glomerular pathologic states [26]. Based on genetic studies, copy number variations in CFHR5 is implicated in C3GN [8,[27][28], but signi cant enrichment of disease-associated rare variants is less [29]. The c.508G > A in the gene CFHR5 generates a nonsynonymous alteration at amino acid position 170 (Val in wild-type and Met in mutant), which is strictly conserved among organisms.…”

Das Komplementsystem: von den Grundlagen zur klinischen Bedeutung

“…Die Pathogenese der C3GN ist heterogen und wird sowohl durch Autoimmunreaktionen als auch genetische Faktoren induziert [91]. Ähnlich wie bei aHUS können auch Patienten mit C3G Varianten in den Genen CFH, CFHR1-CFHR5, CFI, MCP/CD46 und C3 aufweisen [91,92]. Im Gegensatz zu aHUS beeinträchtigen diese Mutationen bei C3G normalerweise nicht die Komplementregulation auf Endothelzellen, sondern resultieren in einer Fehlregulation des alternativen Komplementwegs in der Flüssigphase oder auf bestimmten glomerulären Oberflächen (GBM, Mesangium).…”