Alternative titles; symbols
HGNC Approved Gene Symbol: CFHR3
Cytogenetic location: 1q31.3 Genomic coordinates (GRCh38) : 1:196,774,840-196,795,407 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q31.3 | {Hemolytic uremic syndrome, atypical, susceptibility to} | 235400 | Autosomal dominant; Autosomal recessive | 3 |
| {Macular degeneration, age-related, reduced risk of} | 603075 | Autosomal dominant | 3 |
Human complement factor H (CFH; 134370) and the 5 factor H-related proteins, CFHR1 (134371), CFHR2 (600889), CFHR3, CFHR4 (605337), and CFHR5 (608593), are exclusively composed of highly-related short consensus repeats (SCRs), each of which contains 4 cysteine residues and additional conserved amino acids.
By screening a liver cDNA library with fragments of CFH, Skerka et al. (1993) isolated a cDNA encoding CFHR3, which they termed DOWN16. The deduced 331-amino acid protein has a 19-amino acid signal peptide, 4 N-linked glycosylation sites, and 5 SCRs. SCR 1 and 2 of CFHL3 are homologous to SCR 6 and 7 of CFH, whereas SCR 3, 4, and 5 of CFHR3 are somewhat less homologous to SCR 8, 19, and 20 of CFH. Northern blot analysis revealed expression of a 1.4-kb CFHR3 transcript in liver. Autoradiographic analysis determined that CFHR3 is secreted as a 37.5-kD protein.
Hellwage et al. (1999) determined by affinity chromatography that serum CFHR3, but not CFHR4, binds to heparin. However, Biacore (surface plasmon resonance) and opsonization analyses showed that both proteins bind to C3b and C3d but not to C3c. Both CFHR3 and CFHR4 enhance the cofactor activity of factor H in C3b inactivation.
By radiation hybrid analysis, Diaz-Guillen et al. (1999) determined that the CFHR3 gene is closely linked to the CFH gene on chromosome 1q31-q32.1.
Hughes et al. (2006) genotyped polymorphisms spanning the cluster of CFH and 5 CFH-related genes on chromosome 1q23 in 173 individuals with severe neovascular age-related macular degeneration (ARMD; see 603075) and 170 elderly controls with no signs of ARMD. They found that a haplotype carrying an 84-kb deletion of the CFHR1 and and CFHR3 genes (605336.0001) was associated with decreased risk of ARMD.
Extending their previous work (see Hughes et al., 2006), Zipfel et al. (2007) found that the CFHR1/CFHR3 deletion was associated with an increased risk of atypical hemolytic-uremic syndrome (aHUS; 235400) in 2 independent European cohorts. Zipfel et al. (2007) noted that the present study showed an opposite effect for the variant from that of Hughes et al. (2006), which may be due to a disease-modifying action of the deletion or linkage disequilibrium between the deletion and other susceptibility alleles. Of 147 patients with aHUS, 121 of whom had previously been reported by Zipfel et al. (2007), Jozsi et al. (2008) identified serum anti-CFH autoantibodies in 16 (11%); 14 lacked CFHR1/CFHR3 completely and 2 showed extremely low CFHR1/CFHR3 plasma levels. The findings illustrated a new combination of 2 susceptibility factors for the development of aHUS.
In 711 individuals with ARMD and 1,041 controls, Raychaudhuri et al. (2010) reproduced associations at the Y402H allele (134370.0008), using rs10801555 as a proxy, and rs1410996 (134370.0016), using rs10737680 as a proxy, but observed modest evidence for association with the CFHR1/CFHR3 deletion (p = 7.0 x 10(-21)). Logistic regression conditioned on rs10737680 resulted in substantially mitigated statistical strength for the protective effect of the CFHR1/CFHR3 deletion, suggesting that the CFHR1/CFHR3 deletion and rs10737680 were not entirely independent. Haplotype analysis demonstrated that both markers tag a collection of low-risk haplotypes, but neither tags all of them perfectly, suggesting that there could be 1 or more not-yet-identified variants that better explain disease risk. Raychaudhuri et al. (2010) favored the parsimonious explanations of a single functional allele in high correlation with rs10737680 acting on all protective haplotypes or of a risk variant acting on the intermediate risk haplotypes. In response, Hughes et al. (2010) noted that the finding of a lower statistical significance for the CFHR1/CFHR3 deletion than for rs10801555 or rs10737680 was a reflection of allele frequencies rather than effect size. The authors suggested that parsimonious explanations with the fewest functional elements are unnecessarily restrictive and noted that functional studies support a minimum of 3 factors.
Associations Pending Confirmation
Davila et al. (2010) performed a genomewide association study for susceptibility to meningococcal disease using 475 patients and 4,703 controls from the UK, followed by 2 replication studies for the most significant SNPs in western and southern European cohorts consisting of 968 patients and 1,376 controls. They identified SNPs within CFH (rs1065489; P = 2.2 x 10(-11)) and CFHR3 (rs426736; P = 4.6 x 10(-13)) that replicated independently in both cohorts. The SNP in CFH, rs1065489, is nonsynonymous and results in an asp936-to-glu substitution. Davila et al. (2010) noted that the causative agent of meningococcal disease, Neisseria meningitidis, evades complement-mediated killing by binding to host CFH. They proposed that genetic variation in these regulators of complement activation plays a role in determining the occurrence of invasive versus asymptomatic colonization by this organism.
Hughes et al. (2006) identified an 84-kb deletion that occurred between 2 virtually identical 29-kb segments of duplication and was located downstream of the CFH gene and upstream of the CFHR4 gene. By sequence analysis in 3 individuals who were homozygous for the deletion, Zipfel et al. (2007) showed that the deletion resulted from nonallelic homologous recombination.
Hughes et al. (2006) found that a haplotype carrying a deletion of the CFHR1 and CFHR3 (605336) genes was associated with decreased risk of age-related macular degeneration (ARMD; see 603075), being present on 20% of chromosomes of controls and 8% of chromosomes of individuals with ARMD. The proteins encoded by these genes were absent in serum of homozygotes. The protective effect of the deletion haplotype could not be attributed to linkage disequilibrium with the Y402H variant of complement factor H (134370.0008) and was replicated in an independent sample.
Extending their previous work (see Hughes et al., 2006), Zipfel et al. (2007) found that the CFHR1/CFHR3 deletion was associated with an increased risk of atypical hemolytic-uremic syndrome (aHUS; 235400) in 2 independent European cohorts. In the first group, 19 (16%) of 121 aHUS patients had the deletion compared to 2 of 100 control individuals. Three of the patients had a homozygous deletion. All patients had normal serum factor H levels. In the second group comprising 66 patients, 28% had the deletion compared to 6% of controls. Ten percent and 2% of patients and controls, respectively, were homozygous for the deletion. In vitro functional expression studies showed that CFHR1/CFHR3-deficient plasma had decreased protective activity against erythrocyte lysis, suggesting a defective regulation of complement activation. Zipfel et al. (2007) noted that the present study showed an opposite effect for the variant from that of Hughes et al. (2006), which may be due to a disease-modifying action of the deletion or linkage disequilibrium between the deletion and other susceptibility alleles. Of 147 patients with aHUS, 121 of whom had previously been reported by Zipfel et al. (2007), Jozsi et al. (2008) identified serum anti-CFH autoantibodies in 16 (11%); 14 lacked CFHR1/CFHR3 completely and 2 showed extremely low CFHR1/CFHR3 plasma levels. The findings illustrated a new combination of 2 susceptibility factors for the development of aHUS.
The CFHR1/CFHR3 deletion exclusively occurs on one of the 2 protective CFH haplotypes, both of which are tagged by the protective allele of single-nucleotide polymorphism rs2274700 (A473A). In a German cohort of 530 ARMD patients, Fritsche et al. (2010) showed that protection against ARMD conferred by delta-CFHR3/CFHR1 was independent of the effects of CFH polymorphisms rs2274700 and rs1061170 (Y402H; 134370.0008). This suggested a functional role of CFHR1 and/or CFHR3 in disease pathogenesis. Fritsche et al. (2010) determined that CFHR3 is a novel human complement regulator that inhibits C3 (120700) convertase activity. CFHR3 displayed antiinflammatory effects by blocking C5A (see 120900) generation and C5A-mediated chemoattraction of neutrophils. In addition, CFHR3 and CFHR1 competed with factor H for binding to the central complement component C3. Thus, deficiency of CFHR3 and CFHR1 resulted in a loss of complement control but enhanced local regulation by factor H. Fritsche et al. (2010) hypothesized that dysregulation of complement may play a central role in ARMD pathology.
Davila, S., Wright, V. J., Khor, C. C., Sim, K. S., Binder, A., Breunis, W. B., Inwald, D., Nadel, S., Betts, H., Carrol, E. D., de Groot, R., Hermans, P. W. M., and 9 others. Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nature Genet. 42: 772-776, 2010. [PubMed: 20694013] [Full Text: https://doi.org/10.1038/ng.640]
Diaz-Guillen, M. A., Rodriguez de Cordoba, S., Heine-Suner, D. A radiation hybrid map of complement factor H and factor H-related genes. Immunogenetics 49: 549-552, 1999. [PubMed: 10380701] [Full Text: https://doi.org/10.1007/s002510050534]
Fritsche, L. G., Lauer, N., Hartmann, A., Stippa, S., Keilhauer, C. N., Oppermann, M., Pandey, M. J., Kohl, J., Zipfel, P. F., Weber, B. H. F., Skerka, C. An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum. Molec. Genet. 19: 4694-4704, 2010. [PubMed: 20843825] [Full Text: https://doi.org/10.1093/hmg/ddq399]
Hellwage, J., Jokiranta, T. S., Koistinen, V., Vaarala, O., Meri, S., Zipfel, P. F. Functional properties of complement factor H-related proteins FHR-3 and FHR-4: binding to the C3d region of C3b and differential regulation by heparin. FEBS Lett. 462: 345-352, 1999. [PubMed: 10622723] [Full Text: https://doi.org/10.1016/s0014-5793(99)01554-9]
Hughes, A. E., Orr, N., Cordell, H. J., Goodship, T. Hughes et al. reply. (Letter) Nature Genet. 42: 555-556, 2010.
Hughes, A. E., Orr, N., Esfandiary, H., Diaz-Torres, M., Goodship T., Chakravarthy, U. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nature Genet. 38: 1173-1177, 2006. Note: Erratum: Nature Genet. 39: 567 only, 2007. [PubMed: 16998489] [Full Text: https://doi.org/10.1038/ng1890]
Jozsi, M., Licht, C., Strobel, S., Zipfel, S. L. H., Richter, H., Heinen, S., Zipfel, P. F., Skerka, C. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111: 1512-1514, 2008. [PubMed: 18006700] [Full Text: https://doi.org/10.1182/blood-2007-09-109876]
Raychaudhuri, S., Ripke, S., Li, M., Neale, B. M., Fagerness, J., Reynolds, R., Sobrin, L., Swaroop, A., Abecasis, G., Seddon, J. M., Daly, M. J. Associations of CFHR1-CFHR3 deletion and a CFH SNP to age-related macular degeneration are not independent. (Letter) Nature Genet. 42: 553-555, 2010. [PubMed: 20581873] [Full Text: https://doi.org/10.1038/ng0710-553]
Skerka, C., Kuhn, S., Gunther, K., Lingelbach, K., Zipfel, P. F. A novel short consensus repeat containing molecule is related to human complement factor H. J. Biol. Chem. 268: 2904-2908, 1993. [PubMed: 8428964]
Zipfel, P. F., Edey, M., Heinen, S., Jozsi, M., Richter, H., Misselwitz, J., Hoppe, B., Routledge, D., Strain, L., Hughes, A. E., Goodship, J. A., Licht, C., Goodship, T. H. J., Skerka, C. Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PLoS Genet. 3: e41, 2007. Note: Electronic Article. [PubMed: 17367211] [Full Text: https://doi.org/10.1371/journal.pgen.0030041]