REVIEW www.jasn.org CFHR Gene Variations Provide Insights in the Pathogenesis of the Kidney Diseases Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy Peter F. Zipfel ,1,2 Thorsten Wiech,3 Emma D. Stea,1 and Christine Skerka 1 1Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany; 2Institute of Microbiology, Friedrich-Schiller-University, Jena, Germany; and 3Section of Nephropathology, Institute of Pathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany ABSTRACT Sequence and copy number variations in the human CFHR–Factor H gene cluster regulation on endothelial surfaces and comprising the complement genes CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, and fluid-phase regulation remains intact. In Factor H are linked to the human kidney diseases atypical hemolytic uremic syn- C3 glomerulopathy, FHR mutants in the drome (aHUS) and C3 glomerulopathy. Distinct genetic and chromosomal alter- context of intact Factor H and FHL1 (the ations, deletions, or duplications generate hybrid or mutant CFHR genes, as well Factor H–like protein) affect complement as hybrid CFHR–Factor H genes, and alter the FHR and Factor H plasma repertoire. regulation in the fluid phase and on the A clear association between the genetic modifications and the pathologic outcome glomerular surface, and FHR mutants is emerging: CFHR1, CFHR3,andFactor H gene alterations combined with intact with duplicated interaction segments CFHR2, CFHR4,andCFHR5 genes are reported in atypical hemolytic uremic syn- form large oligomers, which deregulate drome. But alterations in each of the five CFHR genes in the context of an intact complement and compete with Factor H Factor H gene are described in C3 glomerulopathy. These genetic modifications for surface binding. Thus, C3 glomerulop- influence complement function and the interplay of the five FHR proteins with each athy develops due to unique CFHR gene other and with Factor H. Understanding how mutant or hybrid FHR proteins, Factor variations in the context of an intact Factor H::FHR hybrid proteins, and altered Factor H, FHR plasma profiles cause pathology H gene. is of high interest for diagnosis and therapy. Here, we summarize how modifica- tions in the CFHR gene cluster described JASN 31: 241–256, 2020. doi: https://doi.org/10.1681/ASN.2019050515 for aHUS and C3 glomerulopathy cause specific FHR mutants and how they affect the FHR plasma repertoire. Thereby, this Sequence and copy number variations in Factor H on the endothelial surface is review will focus on (1) providing an over- the human CFHR gene cluster are linked altered. In C3 glomerulopathy, the FHR view of complement initiation, with the to the kidney disorders atypical hemo- mutants and a modified FHR plasma two central enzymatic levels and the various lyticuremicsyndrome(aHUS)andC3 repertoire apparently affect local com- effector actions; (2) the characteristic glomerulopathy,1–6 and are further- plement regulation, inducing cell pro- more associated with IgA nephropathy liferation and chronic inflammation. fi (IgAN), with a retinal disease, and with To evaluate how alterations in the ve Published online ahead of print. Publication date – infections.5 8 These copy number varia- CFHR genes and the Factor H gene cause available at www.jasn.org. tions are caused by deletions, duplications, different renal pathologies, we here link Presentaddress:Dr.EmmaD.Stea,Nephrology, and insertions of gene or chromosomal the genetic scenarios, the specificFHR Dialysis and Transplantation Unit, Department of segments and generate CFHR::CFHR, variants expressed in plasma, with the Emergency and Organ Transplantation, University ‘ ’ CFHR::Factor H,andFactor H::CFHR glomerular changes in these kidney dis- Aldo Moro, Bari, Italy. hybrid genes or CFHR genes with dupli- eases. We summarize the role of FHR Correspondence: Prof. Peter F. Zipfel, Department cated elements and result in FHR hybrid proteins as emerging complement mod- of Infection Biology, Leibniz Institute for Natural Products Research and Infection Biology, Beutenbergstr 1 fi fl or mutant proteins and alter the FHR and ulators, ampli ers, and in ammatory 11a, Jena D-07745, Thueringen, Germany. Email: Factor H plasma repertoire. One clear dif- modifiers. In aHUS FHR mutants and in [email protected] ference is emerging: in aHUS, ultimately autoimmune aHUS pathogenic Factor Copyright © 2020 by the American Society of the protective complement action of H–binding autoantibodies alter Factor H Nephrology JASN 31: 241–256, 2020 ISSN : 1046-6673/3102-241 241 REVIEW www.jasn.org morphologic features of the human AP and the convertase (C2bC4bC3b) of Significance Statement kidney disorders aHUS and C3 glomerul- the LP/CP-pathway use C5 as substrate opathy; (3) giving a brief summary on the and generate C5a and C5b. The human CFHR–Factor H gene cluster organization of the human CFHR–Factor Complement action occurs in the encodes the five FHR proteins that are H gene cluster with the Factor H and the fluid phase and on surfaces and multiple emerging complement and immune mod- fi ulators and the two complement regulators ve CFHR genes and on the structure of regulators control activation and the Factor H and FHL1. Genetic and chromo- the encoded FHR proteins; (4) explaining transition from fluid phase to the surface.9 somal alterations in this cluster are associ- how, in aHUS, CFHR gene variations Both C3 convertases form the inflamma- ated with the human kidney diseases generate Factor H::FHR3, Factor H::FHR1, tory anaphylatoxin C3a and the opsonin atypical hemolytic uremic syndrome and and FHR1::Factor H hybrid proteins and C3b. C3b is handled differently on self and C3 glomerulopathy. Various genetic alter- ations result in the expression of mutant how they alter FHR plasma levels; (5)de- nonself surfaces. C3b deposited on intact and altered FHR proteins, or FHR::Factor H scribing which genetic CFHR changes oc- self surfaces is inactivated by complement and Factor H::FHR hybrid proteins. The cur in C3 glomerulopathy; (6) describing proteases which act together with cofac- modified FHR proteins together with an which FHR hybrid or FHR mutant proteins tors, and inactivated iC3b is further pro- altered FHR and Factor H plasma reper- are expressed in this disease; (7) describing cessed to C3dg and C3d. In addition, C3b toire, which often modify complement action in the fluid phase and cause mor- how altered FHR plasma levels result in C3 when deposited to foreign surfaces ini- phologic alteration in the glomerulus, glomerulopathy; (8) summarizing the new tiates the amplification loop that amplifies provide important views on FHR protein insights into the role of the FHR proteins in C3b deposition. The second enzymatic function in the kidney. IgAN,incomplementcontrolanddisease level with the C5 convertase generates pathology; and (9) providing concluding the potent anaphylatoxin C5a and de- that are causative for the two kidney remarks and an outlook for diagnosis, bio- posits C5b, which initiates the pore- diseases, genetic aHUS and C3 glomerul- marker profiling, and therapy. forming terminal complement complex opathy. The morphologic and cellular al- (TCC) (Figure 1A).13,14 Thus, two enzy- terations, which are caused by deregulated matic steps generate different effector com- complement, are summarized in recent COMPLEMENT: INITIATION, pounds (1) in the form of anaphylatoxins excellent reviews.17,18 The morphologic ENZYMATIC LEVELS, AND C3a and C5a that induce inflammation appearance of aHUS in the glomeruli EFFECTOR PATHWAYS and attract host cells; (2)byopsonization and the preglomerular arterioles can be of target surfaces with C3b; and (3)by characterized as thrombotic microangi- Complement is a central homeotic sys- forming the TCC, which generates a pore tem and defective complement causes and damages the target membrane.15,16 opathy. Best understood is primary many human diseases, in particular the An important challenge is to understand complement-mediated endothelial and kidney diseases aHUS and C3 glomerul- complement regulation and the actions of mesangial cell damage due to dysregulation opathy.9,10 In order to link complement existing regulators and new modulators. of the alternative complement cascade on 19 with CFHR gene variations a brief over- Given that FHR proteins are emerging com- the cell surface. Defective complement view of complement, with the three ac- plement modulators and amplifiers, it is of control on endothelial surfaces results in tivation pathways and with two central interest to define at which specificstepofa cell lysis, followed by thrombus forma- enzymatic checkpoints, is presented pathway and at which checkpoints each tion, loss of mesangial cells, and mesan- (Figure 1A). Activation of the alternative FHR protein acts. The different pathologies giolysis as seen in histology (Figure 1C). pathway occurs spontaneously in the caused by the FHR mutants and hybrids, In the chronic or repair phase, the newly fluid phase and propels on target surfaces; i.e., endothelial damage in aHUS and in formed endothelial cells produce new extra- the lectin and the classic pathways are ini- DEAP-HUS (homozygous CFHR1-CFHR3 cellular matrix, leading to double contours tiated on target surfaces by carbohydrates Deficiency and Autoantibody to Factor H of the glomerular basement membrane and antibodies bound to antigens.9–11 Positive), and inflammatory and prolifera- (GBM) thickening.17,18 In contrast, in C3 Upon initiation, two subsequently acting tive action in