Alternative titles; symbols
HGNC Approved Gene Symbol: CFHR5
Cytogenetic location: 1q31.3 Genomic coordinates (GRCh38) : 1:196,975,034-197,009,678 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q31.3 | Nephropathy due to CFHR5 deficiency | 614809 | Autosomal dominant | 3 |
CFHR5 is a complement activator that binds to necrotic human endothelial cells, activated mesangial cells, and extracellular matrix (Rudnick et al., 2018).
McRae et al. (2001) identified a novel human plasma protein homologous to complement factor H (CFH; 134370) and related proteins, which they designated FHR5. The protein is a universal component of complement deposits, when complement is detected immunohistochemically in vivo. McRae et al. (2001) identified CFHL5 by a monoclonal antibody raised using pathologic human glomerular preparations as the immunogen. CFHL5 was purified by affinity chromatography from complement-lysed erythrocytes and the peptide sequence was obtained. The cDNA was cloned from a human liver library; the deduced protein contains 551 amino acids organized into 9 short consensus repeat (SCR) motifs. CFHL5 is unique among the factor H-related proteins in that it contains 5 additional SCRs, homologous to SCRs 10-14 of factor H, which are not present in the other factor H-related proteins.
By FISH, radiation hybrid mapping, and genomic sequence analysis, McRae et al. (2002) mapped the CFHL5 gene to chromosome 1q32 between CFHL2 (600889) and the noncomplement protein factor XIIIb (F13B; 134580), within the regulators of complement activation (RCA) gene cluster.
McRae et al. (2001) found that recombinant CFHL5, expressed in insect cells, bound C3b (120700) in vitro. The strong association of CFHL5 with tissue complement deposits in vivo suggested that CFHL5 functions in complement regulation.
Abrera-Abeleda et al. (2006) noted that the first 2 SCRs of CFHR5 are similar to SCRs 6 and 7 of CFH and therefore have C-reactive protein (CRP; 123260)- and heparan-binding properties.
Rudnick et al. (2018) showed that human FHR5 bound laminin-521, the major constituent of glomerular basement membrane, and mesangial laminin-211. They also identified malondialdehyde-acetaldehyde (MAA) epitopes, which are exposed on the surface of human necrotic cells, as FHR5 ligands. Deletion analysis revealed that FHR5 bound laminin-521, heparin, human necrotic cells, and MAA epitopes via SCRs 5 through 7. In contrast, FHR5 bound C3b via SCRs 8 and 9. FHR5 competed with factor H for binding to oxidation-specific MAA epitopes and activated complement on MAA surfaces.
For information on this gene family, see 134371.
Among 22 patients with biopsy-proven C3 glomerulopathy-3 (C3G3; 614809), Abrera-Abeleda et al. (2006) found an association with 3 SNPs in the CFHR5 gene. The findings strengthened the hypothesis that complement control plays a role in the pathogenesis of the disease.
In 26 individuals with C3G3 from 11 families of Cypriot origin, Gale et al. (2010) identified a heterozygous duplication of exons 2 and 3 of the CFHR5 gene (608593.0001). The internal duplication was not seen in a set of 102 controls, but was found in 1 of 1,015 Cypriot controls. Although the precise pathomechanism was unclear, the findings of abnormal complement deposition in patient renal biopsies indicated a defect in the regulation of C3 (120700).
Athanasiou et al. (2011) identified a heterozygous founder exon 2-3 duplication in the CFHR5 gene in several additional families of Cypriot origin with C3G3. Functional studies of the variant and studies of patient cells were not performed.
Associations Pending Confirmation
In 3 (4.6%) of 65 unrelated patients with atypical hemolytic uremic syndrome (AHUS; see 235400), Westra et al. (2012) identified 3 different heterozygous missense variants in the CFHR5 gene (608593.0003-608593.0005). Westra et al. (2012) suggested that the variants may result in decreased complement regulation, although functional studies were not performed. The CFHR5 gene was chosen for study because of its role in other glomerular diseases (Abrera-Abeleda et al., 2006; Gale et al., 2010). Westra et al. (2012) also cited a study that found CFHR5 variants in 2 (1.4%) of 144 patients with AHUS (Maga et al., 2010), suggesting an association between variation in this gene and AHUS.
By linkage and candidate gene analyses in 2 Cypriot families with C3 glomerulopathy-3 (C3G3; 614809), Gale et al. (2010) identified a heterozygous duplication of exons 2 and 3 of the CFHR5 gene, predicting a novel protein with duplicated SCR domains 1 and 2. This mutant protein was detected in patient serum. The internal duplication was not seen in a set of 102 controls, but was found in 1 of 1,015 Cypriot controls. Screening of this gene in additional patients of Cypriot origin identified several more with the same duplication. In total, 26 patients from 11 ostensibly unrelated families with renal disease carried the mutation. Haplotype analysis performed on 5 families indicated a founder effect. All had microscopic hematuria, and many developed macroscopic hematuria following upper respiratory tract infections. Renal biopsies showed glomerulonephritis with C3 (120700) deposits in the subendothelium and mesangium. The risk of progression appeared to be greater in men than in women with the disease. In vitro functional expression studies showed that the mutant protein bound less well to surface-bound complement compared to wildtype. However, the mutant protein circulated and showed enhanced complement factor I (CFI; 217030) compared to wildtype CFHR5. Although the precise pathomechanism was unclear, the findings of abnormal complement deposition in patient renal biopsies indicated a defect in regulation of C3.
Mutation Function
Kadkhodayi-Kholghi et al. (2020) noted that the exon 2-3 duplication in the CFHR5 gene results in the production of an elongated FHR5 protein with 2 extra N-terminal SCR-1/2 domains in tandem. Using detailed structural analysis, the authors determined that FHR5 forms dimers and is a complement deregulator that competitively inhibits factor H (CFH; 134370), an important regulator of C3b (120700) activation at host cell surfaces. They provided evidence that the duplication mutation alters the FHR5 dimer structure and that the mutant protein competes with factor H binding and thus antagonizes the regulatory function of factor H, resulting in an amplification of complement activation at host cell surfaces when C3 deposition reaches a critical density. The findings were consistent with a gain-of-function effect rather than a deficiency.
In a girl with C3 glomerulopathy-3 (C3G3; 614809) and persistent renal disease following a streptococcal infection, Vernon et al. (2012) identified a heterozygous 1-bp insertion (485dupA) in exon 4 of the CFHR5 gene, resulting in a frameshift and premature termination (Glu163ArgfsTer34). The mutation was not found in 198 controls in this study, but was present in her unaffected mother and sister. The patient presented at age 7 years with dark-colored proteinuria after a 10-day history of fever and sore throat. After treatment for the infection, she had persistent hematuria and proteinuria. Nine months later, kidney biopsy showed mesangial hypercellularity, segmental endocapillary hypercellularity, and segmental capillary wall double contours. There was mesangial and capillary deposition of C3 (120700), C9 (120940), and CFHR5. Electron microscopy showed thickening of the glomerular basement membranes, intramembranous electron-dense deposits, and subendothelial and subepithelial deposits. Serum CFHR5 was decreased to 37.3% of control values. Treatment with an angiotensin receptor (see 106165) blocker resulted in improved kidney function. The presence of the mutation in her unaffected mother and sister suggested that it is not sufficient to cause disease, but likely acts as a susceptibility factor for the development of glomerulonephritis.
This variant is classified as a variant of unknown significance because its contribution to atypical hemolytic uremic syndrome (AHUS; see 235400) has not been confirmed.
In a man who developed AHUS at age 45 years, Westra et al. (2012) identified a heterozygous 1308G-T transversion in the CFHR5 gene, resulting in a trp436-to-cys (W436C) substitution in the SCR7 domain. The mutation was not found in 152 controls, nor in the exomes of 5,400 control individuals from large databases. The patient developed end-stage renal failure necessitating transplantation; there was evidence of disease recurrence in the graft. Functional studies were not performed.
This variant is classified as a variant of unknown significance because its contribution to atypical hemolytic uremic syndrome (AHUS; see 235400) has not been confirmed.
In a girl who developed atypical hemolytic uremic syndrome at age 8 years, Westra et al. (2012) identified a heterozygous 314T-G transversion in the CFHR5 gene, resulting in a leu105-to-arg (L105R) substitution in SCR2. The mutation was not found in 149 controls, nor in the exomes of 5,400 control individuals from large databases. The patient had end-stage renal failure necessitating transplantation; there was evidence of disease recurrence in the graft. Serum analysis showed significantly increased sC5b-9 activity levels, indicating increased complement activation. Functional studies were not performed.
This variant is classified as a variant of unknown significance because its contribution to atypical hemolytic uremic syndrome (AHUS; see 235400) has not been confirmed.
In a patient with AHUS, Westra et al. (2012) identified a heterozygous 583T-A transversion in the CFHR5 gene, resulting in a ser195-to-thr (S195T) substitution in the SCR3 domain. The mutation was not found in 146 controls, nor in the exomes of 5,400 control individuals from large databases. No clinical information was available for this patient, and functional studies were not performed.
Abrera-Abeleda, M. A., Nishimura, C., Smith, J. L. H., Sethi, S., McRae, J. L., Murphy, B. F., Silvestri, G., Skerka, C., Jozsi, M., Zipfel, P. F., Hageman, G. S., Smith, R. J. H. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J. Med. Genet. 43: 582-589, 2006. [PubMed: 16299065] [Full Text: https://doi.org/10.1136/jmg.2005.038315]
Athanasiou, Y., Voskarides, K., Gale, D. P., Damianou, L., Patsias, C., Zavros, M., Maxwell, P. H., Cook, H. T., Demosthenous, P., Hadjisavvas, A., Kyriacou, K., Zouvani, I., Pierides, A., Deltas, C. Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees. Clin. J. Am. Soc. Nephrol. 6: 1436-1446, 2011. [PubMed: 21566112] [Full Text: https://doi.org/10.2215/CJN.09541010]
Gale, D. P., Goicoechea de Jorge, E., Cook, H. T., Martinez-Barricarte, R., Hadjisavvas, A., McLean, A. G., Pusey, C. D., Pierides, A., Kyriacou, K., Athanasiou, Y., Voskarides, K., Deltas, C., Palmer, A., Fremeaux-Bacchi, V., Rodriguez de Cordoba, S., Maxwell, P. H., Pickering, M. C. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376: 794-801, 2010. [PubMed: 20800271] [Full Text: https://doi.org/10.1016/S0140-6736(10)60670-8]
Kadkhodayi-Kholghi, N., Bhatt, J. S., Gor, J., McDermott, L. C., Gale, D. P., Perkins, S. J. The solution structure of the complement deregulator FHR5 reveals a compact dimer and provides new insights into CFHR5 nephropathy. J. Biol. Chem. 295: 16342-16358, 2020. [PubMed: 32928961] [Full Text: https://doi.org/10.1074/jbc.RA120.015132]
Maga, T. K., Nishimura, C. J., Weaver, A. E., Frees, K. L., Smith, R. J. H. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum. Mutat. 31: E1445-E1460, 2010. Note: Electronic Article. [PubMed: 20513133] [Full Text: https://doi.org/10.1002/humu.21256]
McRae, J. L., Cowan, P. J., Power, D. A., Mitchelhill, K. I., Kemp, B. E., Morgan, B. P., Murphy, B. F. Human factor H-related protein 5 (FHR-5): a new complement-associated protein. J. Biol. Chem. 276: 6747-6754, 2001. [PubMed: 11058592] [Full Text: https://doi.org/10.1074/jbc.M007495200]
McRae, J. L., Murphy, B. E., Eyre, H. J., Sutherland, G. R., Crawford, J., Cowan, P. J. Location and structure of the human FHR-5 gene. Genetica 114: 157-161, 2002. [PubMed: 12041828] [Full Text: https://doi.org/10.1023/a:1015114512924]
Rudnick, R. B., Chen, Q., Stea, E. D., Hartmann, A., Papac-Milicevic, N., Person, F., Wiesener, M., Binder, C. J., Wiech, T., Skerka, C., Zipfel, P. F. FHR5 binds to laminins, uses separate C3b and surface-binding sites, and activates complement on malondialdehyde-acetaldehyde surfaces. J. Immun. 200: 2280-2290, 2018. [PubMed: 29483359] [Full Text: https://doi.org/10.4049/jimmunol.1701641]
Vernon, K. A., Goicoechea de Jorge, E., Hall, A. E., Fremeaux-Bacchi, V., Aitman, T. J., Cook, H. T., Hangartner, R., Koziell, A., Pickering, M. C. Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency. Am. J. Kidney Dis. 60: 121-125, 2012. [PubMed: 22503529] [Full Text: https://doi.org/10.1053/j.ajkd.2012.02.329]
Westra, D., Vernon, K. A., Volokhina, E. B., Pickering, M. C., van de Kar, N. C. A. J., van den Heuvel, L. P. Atypical hemolytic uremic syndrome and genetic aberrations in the complement factor H-related 5 gene. J. Hum. Genet. 57: 459-464, 2012. [PubMed: 22622361] [Full Text: https://doi.org/10.1038/jhg.2012.57]