{"gene":"CFHR3","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2006,"finding":"Deletion of CFHR3 and CFHR1 results in absence of both proteins from serum in homozygotes, establishing that these genes encode the serum proteins and that the deletion is a functional null for both.","method":"Serum protein detection in homozygous deletion carriers; genomic analysis of deletion haplotype","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein absence confirmed in homozygotes, replicated in independent sample, but single lab for the protein measurement","pmids":["16998489"],"is_preprint":false},{"year":2007,"finding":"Homozygous deletion of CFHR3 and CFHR1 impairs protection of erythrocytes from complement activation, as demonstrated in serum of aHUS patients deficient in both proteins, suggesting a regulatory role for CFHR1 and CFHR3 in complement activation.","method":"Functional complement activation assay on erythrocytes using patient serum from CFHR1/CFHR3-deficient individuals","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay in patient serum, two independent cohorts, but results conflate CFHR1 and CFHR3 without isolating individual protein contributions","pmids":["17367211"],"is_preprint":false},{"year":2010,"finding":"The genomic region encoding CFHR3 and CFHR1 is flanked by long homologous repeats (containing LINEs/retrotransposons), and nonallelic homologous recombination between these repeats leads to an ~84 kb deletion removing both genes.","method":"Genomic sequencing and amplification analysis of deletion breakpoints in affected individuals","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — sequence-level characterization of deletion mechanism, single study","pmids":["17367211"],"is_preprint":false},{"year":2011,"finding":"A hybrid CFH/CFHR3 gene formed by microhomology-mediated end joining produces a 24-SCR protein that is secreted with normal fluid-phase complement regulatory activity but markedly impaired complement regulation at cell surfaces, despite increased heparin binding, demonstrating that structural integrity of the full factor H molecule is required for cell-surface complement regulation.","method":"Genomic characterization of deletion/hybrid gene; functional protein assays (fluid-phase activity, cell-surface regulation, heparin binding) on the hybrid CFH/CFHR3 protein","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — protein biochemistry with multiple orthogonal functional assays (fluid-phase vs. cell-surface activity, heparin binding) on the defined hybrid protein product","pmids":["22058112"],"is_preprint":false},{"year":2016,"finding":"FHR-3 binds to C3d and thereby competitively inhibits the interaction between C3d and complement receptor CD21 (CR2), blocking B cell coreceptor complex (CD19/CD21/CD81) colocalization with the BCR. This prevents CD19 and Akt phosphorylation and Ca2+ release, neutralizing the adjuvant effect of C3d on B cell activation.","method":"Laser-scanning microscopy and automated image analysis; intracellular phosphorylation assays (CD19, Akt) in Raji cells; Ca2+ release assays in peripheral B cells; competitive binding studies with FHR-3, FHR-1, and factor H","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal functional assays (imaging, phosphorylation, Ca2+ flux) in both cell lines and primary cells, with mechanistic specificity (FHR-3 but not FHR-1 or FH has this effect)","pmids":["27279373"],"is_preprint":false},{"year":2016,"finding":"FHR-3 competes with complement factor H (FH) for binding to C3b. A monoclonal antibody (RETC-2) that blocks FHR-3 binding to C3b results in increased FH binding to C3b, establishing a direct competitive relationship between FHR-3 and FH at C3b.","method":"Monoclonal antibody generation; binding competition assays between FHR-3 and FH for C3b; immunostaining of human donor retina showing local FHR-3 production by microglia/macrophages","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct competition binding assay with specific mAb modulation, supported by localization data, single lab","pmids":["27965669"],"is_preprint":false},{"year":2016,"finding":"FHR-3 serum levels are determined predominantly by CFHR3 gene copy number under normal conditions; the mean FHR-3 concentration (~19 nM) is approximately 132-fold lower than FH in the same samples, and FHR-3 does not behave as a major acute-phase response protein.","method":"Specific anti-FHR-3 monoclonal antibodies generated and used in quantitative ELISA; gene copy number variation determined in healthy donors; sepsis cohort acute-phase analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative protein measurement with gene copy number correlation using specific mAbs, single lab, multiple methods within study","pmids":["27007437"],"is_preprint":false},{"year":2018,"finding":"The CFHR3*B allele is a high-expression allele associated with increased aHUS risk, producing approximately twofold more FHR-3 protein than the CFHR3*A allele (a low-expression allele), and elevated FHR-3 plasma levels in aHUS patients with the same CFHR3 genotype compared to controls, suggesting that increased FHR-3 alters the FH/FHR-3 balance to impair FH regulatory function.","method":"Specific ELISA for FHR-3 quantification in 218 patients with at least one CFHR3 copy; genotyping for CFHR3 alleles (*A, *B, *Del) in controls and aHUS patients","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative protein measurements across genotype groups in large patient cohort, single lab, ELISA method","pmids":["29740447"],"is_preprint":false},{"year":2012,"finding":"A hybrid CFHR3-1 gene (formed by gene duplication events at the CFHR3/CFHR1 locus) is associated with complement-mediated glomerulonephritis in an autosomal dominant pattern, and normal copies of both CFHR3 and CFHR1 are present alongside the hybrid gene in affected individuals, linking increased copy number/hybrid gene at this locus to dysregulated complement activation.","method":"Copy number analysis across CFHR3 and CFHR1 loci; identification and characterization of hybrid CFHR3-1 gene in affected family members with complement-mediated GN","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic characterization of hybrid gene with disease association, but functional mechanism of the hybrid protein not fully characterized in vitro","pmids":["22626820"],"is_preprint":false},{"year":2022,"finding":"A CFHR3 SNP (rs75703017) protects from meningococcal disease by decreasing circulating FH concentrations; mechanistically, deletion of this SNP increases FH expression in hepatocytes by preventing promoter inhibition, as established by dual-luciferase reporter assays and CRISPR gene editing.","method":"GWAS sequencing and imputation; dual-luciferase promoter assays; CRISPR gene editing in hepatocytes; FH protein quantification","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — causal variant validated by dual orthogonal experimental approaches (luciferase assay + CRISPR editing) demonstrating promoter-level regulation of FH expression by a CFHR3 intronic SNP","pmids":["36007525"],"is_preprint":false},{"year":2014,"finding":"The CFHR3-1 deletion (CFHR3-1Δ) is associated with higher serum CFH levels and lower complement activation (lower C3a), and CFH levels negatively correlate with mesangial C3 deposition in IgAN patients, suggesting that CFHR3 (and CFHR1) modulate complement activation by influencing the FH/FHR balance in vivo.","method":"Genotype-phenotype correlation analysis in 1178 IgAN patients; serum CFH, C3, and C3a measurement; linkage analysis of rs6677604-A allele with CFHR3-1Δ","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large cohort genotype-phenotype correlation with complement protein quantification, but observational rather than interventional","pmids":["25205734"],"is_preprint":false},{"year":2022,"finding":"Knockdown of CFHR3 in HCC cells promotes phosphorylation of STAT3 and suppresses p53 expression, promoting cell proliferation, migration, and invasion; miR-590-3p binds the 3'UTR of CFHR3 to downregulate its expression; STAT3 inhibitor (S3I-201) attenuates the malignant phenotypes caused by CFHR3 knockdown.","method":"CFHR3 stable knockdown in HCC cells; miR-590-3p 3'UTR binding assay; STAT3 phosphorylation assays; cell proliferation, migration, and invasion assays; STAT3 inhibitor rescue experiment","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple cellular assays with pathway rescue, single lab, mechanism in cancer cell lines may not reflect canonical complement biology","pmids":["35852862"],"is_preprint":false},{"year":2000,"finding":"Sequence analysis of 221 kb of human genomic DNA defined the complete exon-intron structure of CFHR3 (fHR-3), established that the majority of SCR-encoding exons follow single-exon/single-SCR architecture with conserved splice phasing, and identified genomic duplications shared between CFH and CFHR3 exons that arose after rodent-primate divergence via retrotransposition and exon duplication.","method":"Genomic sequence analysis of PAC clone-derived sequence; RUMMAGE-DP automated annotation; Alu/L1 repeat dating","journal":"Molecular immunology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/sequence analysis only, no functional protein experiments","pmids":["10781834"],"is_preprint":false}],"current_model":"CFHR3 encodes a soluble complement regulator (FHR-3) that competes with complement factor H (FH) for binding to C3b and C3d: FHR-3 binds C3d to block CD21-mediated B cell coreceptor activation, competes with FH at C3b to modulate alternative pathway regulation, and its plasma concentration (determined largely by CFHR3 gene copy number and allele type) sets the FH/FHR-3 balance that governs complement activity; a CFHR3 intronic SNP additionally controls FH expression at the transcriptional level in hepatocytes, linking CFHR3 genetic variation to systemic complement regulation and susceptibility to diseases including AMD, aHUS, and IgA nephropathy."},"narrative":{"mechanistic_narrative":"CFHR3 encodes FHR-3, a soluble plasma complement regulator that fine-tunes alternative-pathway activity by competing with complement factor H (FH) for shared ligands [PMID:27965669]. FHR-3 binds C3b and directly competes with FH for this interaction, such that blocking FHR-3 binding increases FH occupancy at C3b, positioning FHR-3 as a modulator of the FH/FHR-3 balance that governs complement regulation [PMID:27965669]. FHR-3 also binds C3d and competitively displaces it from complement receptor CD21 (CR2), preventing assembly of the CD19/CD21/CD81 B cell coreceptor with the BCR and thereby blocking CD19 and Akt phosphorylation and Ca2+ flux — an effect specific to FHR-3 and not shared by FHR-1 or FH — which neutralizes the C3d adjuvant signal on B cells [PMID:27279373]. FHR-3 plasma concentration is set predominantly by CFHR3 gene copy number and allele type, with a high-expression CFHR3*B allele producing roughly twofold more protein and associating with aHUS risk by shifting the FH/FHR-3 balance to impair FH regulation [PMID:27007437, PMID:29740447]. Beyond its protein product, the CFHR3 locus controls FH itself: an intronic SNP (rs75703017) regulates FH expression at the transcriptional level in hepatocytes through promoter inhibition, so that deletion of the SNP raises FH and protects from meningococcal disease [PMID:36007525]. Genomic instability at the locus — driven by flanking homologous repeats — generates a common CFHR3/CFHR1 deletion that removes both proteins from serum and impairs protection of erythrocytes from complement activation, and also produces hybrid genes associated with complement-mediated glomerulonephritis [PMID:16998489, PMID:17367211, PMID:22626820]. Through these genetic and protein-level mechanisms, CFHR3 variation is linked to aHUS, IgA nephropathy, and complement-mediated glomerulonephritis [PMID:29740447, PMID:22626820, PMID:25205734].","teleology":[{"year":2000,"claim":"Before any functional work, the gene architecture had to be defined; sequencing the locus established the exon-intron and SCR-module organization of CFHR3 and revealed its evolutionary origin from CFH-related duplications.","evidence":"Genomic sequence analysis of PAC clones with automated annotation and repeat dating","pmids":["10781834"],"confidence":"Low","gaps":["Computational/sequence analysis only, no functional protein data","Does not establish the protein's biochemical activity or ligands"]},{"year":2006,"claim":"It was unknown whether the CFHR3/CFHR1 genes encode detectable serum proteins; demonstrating their complete absence in homozygous deletion carriers established the genes as functional and defined a natural null.","evidence":"Serum protein detection in homozygous deletion carriers with genomic analysis of the deletion haplotype","pmids":["16998489"],"confidence":"Medium","gaps":["Does not isolate FHR-3 from FHR-1 contributions","No molecular function assigned to either protein"]},{"year":2007,"claim":"The physiological consequence of losing these proteins was unclear; patient serum lacking both showed impaired protection of erythrocytes from complement, implicating CFHR3/CFHR1 in complement regulation.","evidence":"Functional complement activation assay on erythrocytes using serum from CFHR1/CFHR3-deficient aHUS patients","pmids":["17367211"],"confidence":"Medium","gaps":["Conflates CFHR1 and CFHR3 without isolating individual contributions","Patient serum context confounds with disease background"]},{"year":2010,"claim":"The basis for the recurrent deletion was undefined; breakpoint sequencing showed it arises by nonallelic homologous recombination between flanking repeats, explaining the locus's genomic instability.","evidence":"Genomic sequencing and amplification analysis of deletion breakpoints","pmids":["17367211"],"confidence":"Medium","gaps":["Single study","Does not address functional consequences of the deletion at protein level"]},{"year":2011,"claim":"To dissect what structural features control surface complement regulation, a CFH/CFHR3 hybrid protein was characterized, showing retained fluid-phase activity but lost cell-surface regulation, establishing that full FH structural integrity is required for surface control.","evidence":"Genomic characterization plus orthogonal functional assays (fluid-phase activity, cell-surface regulation, heparin binding) on the hybrid protein","pmids":["22058112"],"confidence":"High","gaps":["Concerns a hybrid product rather than native FHR-3","Does not define native FHR-3 ligand specificity"]},{"year":2012,"claim":"Whether locus rearrangements beyond deletion cause disease was open; a hybrid CFHR3-1 gene present alongside normal gene copies was found in autosomal dominant complement-mediated glomerulonephritis, linking increased copy/hybrid gene to complement dysregulation.","evidence":"Copy number analysis and hybrid gene characterization in an affected family","pmids":["22626820"],"confidence":"Medium","gaps":["Functional mechanism of the hybrid protein not characterized in vitro","Single family"]},{"year":2014,"claim":"The in vivo direction of the FH/FHR balance effect was unproven; in IgAN patients the CFHR3-1 deletion correlated with higher serum FH, lower C3a, and reduced mesangial C3 deposition, indicating CFHR3 modulates complement activation by shifting this balance.","evidence":"Genotype-phenotype correlation in 1178 IgAN patients with serum CFH/C3/C3a measurement","pmids":["25205734"],"confidence":"Medium","gaps":["Observational, not interventional","Cannot separate CFHR3 from CFHR1 in the deletion"]},{"year":2016,"claim":"FHR-3's molecular targets and a B-cell function were undefined; FHR-3 was shown to bind C3d and block C3d-CD21 interaction, preventing B cell coreceptor assembly and signaling, and to compete with FH at C3b, defining its dual ligand engagement.","evidence":"Imaging, phosphorylation and Ca2+ flux assays in B cells; competition binding assays with a blocking mAb; retinal localization","pmids":["27279373","27965669"],"confidence":"High","gaps":["Quantitative contribution of each ligand interaction in vivo not resolved","C3b competition shown biochemically without surface-regulation outcome"]},{"year":2016,"claim":"The determinants of circulating FHR-3 were unknown; quantitative ELISA showed serum FHR-3 is set mainly by gene copy number, is ~132-fold lower than FH, and is not a major acute-phase protein.","evidence":"Specific anti-FHR-3 mAb ELISA with gene copy number determination and sepsis cohort analysis","pmids":["27007437"],"confidence":"Medium","gaps":["Single lab quantification","Does not link concentration directly to a functional outcome"]},{"year":2018,"claim":"Whether allelic expression differences drive disease risk was open; the high-expression CFHR3*B allele produced ~twofold more FHR-3 and associated with elevated FHR-3 and aHUS risk, supporting a dosage-dependent impairment of FH regulation.","evidence":"FHR-3 ELISA across CFHR3 genotypes in 218 patients with allele genotyping in controls and aHUS","pmids":["29740447"],"confidence":"Medium","gaps":["Mechanistic link between elevated FHR-3 and impaired FH function inferred, not directly demonstrated","Single ELISA platform"]},{"year":2022,"claim":"The locus's influence on FH itself was unexplained; an intronic CFHR3 SNP was shown to regulate hepatocyte FH expression via promoter inhibition, with SNP deletion raising FH and protecting from meningococcal disease.","evidence":"GWAS imputation, dual-luciferase promoter assays, and CRISPR editing in hepatocytes with FH quantification","pmids":["36007525"],"confidence":"High","gaps":["Defines a transcriptional mechanism distinct from FHR-3 protein function","Does not address tissues beyond hepatocytes"]},{"year":2022,"claim":"A non-complement role was probed in cancer; CFHR3 knockdown in HCC cells activated STAT3 and suppressed p53 to promote proliferation/migration/invasion, with miR-590-3p targeting its 3'UTR and a STAT3 inhibitor rescuing the phenotype.","evidence":"Stable knockdown, 3'UTR binding assay, STAT3 phosphorylation, migration/invasion and inhibitor rescue assays in HCC cell lines","pmids":["35852862"],"confidence":"Medium","gaps":["Single lab in cancer cell lines, may not reflect complement biology","No in vivo validation of the STAT3/p53 axis"]},{"year":null,"claim":"How the competing roles of FHR-3 protein (C3b/C3d competition) and CFHR3-locus transcriptional control of FH integrate quantitatively to set net complement activity in specific tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling protein-level competition with locus-level FH regulation","Tissue-specific contributions of FHR-3 vs FH not quantified","Structural basis of FHR-3 ligand binding not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,4,5]}],"complexes":[],"partners":["C3B","C3D","CFH","CD21"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q02985","full_name":"Complement factor H-related protein 3","aliases":["DOWN16","H factor-like protein 3"],"length_aa":330,"mass_kda":37.3,"function":"Might be involved in complement regulation","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q02985/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFHR3","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1165,"dependency_fraction":0.0034334763948497852},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CFHR3","total_profiled":1310},"omim":[{"mim_id":"610698","title":"MACULAR DEGENERATION, AGE-RELATED, 4; ARMD4","url":"https://www.omim.org/entry/610698"},{"mim_id":"605337","title":"COMPLEMENT FACTOR H-RELATED 4; CFHR4","url":"https://www.omim.org/entry/605337"},{"mim_id":"605336","title":"COMPLEMENT FACTOR H-RELATED 3; CFHR3","url":"https://www.omim.org/entry/605336"},{"mim_id":"603075","title":"MACULAR DEGENERATION, AGE-RELATED, 1; ARMD1","url":"https://www.omim.org/entry/603075"},{"mim_id":"600889","title":"COMPLEMENT FACTOR H-RELATED 2; CFHR2","url":"https://www.omim.org/entry/600889"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"liver","ntpm":366.8}],"url":"https://www.proteinatlas.org/search/CFHR3"},"hgnc":{"alias_symbol":["FHR-3","HLF4","FHR3","DOWN16"],"prev_symbol":["CFHL3"]},"alphafold":{"accession":"Q02985","domains":[{"cath_id":"2.10.70.10","chopping":"32-83","consensus_level":"high","plddt":96.3448,"start":32,"end":83},{"cath_id":"2.10.70.10","chopping":"92-143","consensus_level":"high","plddt":93.5098,"start":92,"end":143},{"cath_id":"2.10.70.10","chopping":"146-206","consensus_level":"high","plddt":91.189,"start":146,"end":206},{"cath_id":"2.10.70.10","chopping":"220-266","consensus_level":"high","plddt":96.1064,"start":220,"end":266},{"cath_id":"2.10.70","chopping":"269-320","consensus_level":"high","plddt":95.0754,"start":269,"end":320}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02985","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02985-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02985-F1-predicted_aligned_error_v6.png","plddt_mean":91.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFHR3","jax_strain_url":"https://www.jax.org/strain/search?query=CFHR3"},"sequence":{"accession":"Q02985","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02985.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02985/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02985"}},"corpus_meta":[{"pmid":"16998489","id":"PMC_16998489","title":"A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration.","date":"2006","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16998489","citation_count":387,"is_preprint":false},{"pmid":"17367211","id":"PMC_17367211","title":"Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome.","date":"2007","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17367211","citation_count":291,"is_preprint":false},{"pmid":"25205734","id":"PMC_25205734","title":"Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy.","date":"2014","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/25205734","citation_count":134,"is_preprint":false},{"pmid":"22626820","id":"PMC_22626820","title":"A hybrid CFHR3-1 gene causes familial C3 glomerulopathy.","date":"2012","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/22626820","citation_count":109,"is_preprint":false},{"pmid":"23613724","id":"PMC_23613724","title":"Determining the population frequency of the CFHR3/CFHR1 deletion at 1q32.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23613724","citation_count":106,"is_preprint":false},{"pmid":"22058112","id":"PMC_22058112","title":"A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22058112","citation_count":77,"is_preprint":false},{"pmid":"18084039","id":"PMC_18084039","title":"Deletion of CFHR3 and CFHR1 genes in age-related macular degeneration.","date":"2007","source":"Human molecular 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and Belatacept for De Novo Atypical Hemolytic Uremic Syndrome Associated With CFHR3-CFHR1 Deletion in a Kidney Transplant Recipient: A Case Report.","date":"2017","source":"Transplantation proceedings","url":"https://pubmed.ncbi.nlm.nih.gov/28104134","citation_count":19,"is_preprint":false},{"pmid":"35852862","id":"PMC_35852862","title":"The miR-590-3p/CFHR3/STAT3 signaling pathway promotes cell proliferation and metastasis in hepatocellular carcinoma.","date":"2022","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/35852862","citation_count":15,"is_preprint":false},{"pmid":"27528699","id":"PMC_27528699","title":"Complement-Regulatory Proteins CFHR1 and CFHR3 and Patient Response to Anti-CD20 Monoclonal Antibody Therapy.","date":"2016","source":"Clinical cancer research : an official journal of the American Association for Cancer 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36007525","citation_count":9,"is_preprint":false},{"pmid":"29728803","id":"PMC_29728803","title":"Acquired thrombotic thrombocytopenic purpura with isolated CFHR3/1 deletion-rapid remission following complement blockade.","date":"2018","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/29728803","citation_count":9,"is_preprint":false},{"pmid":"30945073","id":"PMC_30945073","title":"Altered Peripheral Blood Leucocyte Phenotype and Responses in Healthy Individuals with Homozygous Deletion of FHR1 and FHR3 Genes.","date":"2019","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30945073","citation_count":8,"is_preprint":false},{"pmid":"28991129","id":"PMC_28991129","title":"A Heterozygous CFHR3-CFHR1 Gene Deletion in a Pediatric Patient With Transplant-associated Thrombotic Microangiopathy Who was Treated With Eculizumab.","date":"2018","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28991129","citation_count":8,"is_preprint":false},{"pmid":"26087050","id":"PMC_26087050","title":"Favorable four-yr outcome after renal transplantation in a patient with complement factor H antibody and CFHR1/CFHR3 gene mutation-associated HUS.","date":"2015","source":"Pediatric transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/26087050","citation_count":7,"is_preprint":false},{"pmid":"29225802","id":"PMC_29225802","title":"Effective immunosuppressive management with belatacept and eculizumab in post-transplant aHUS due to a homozygous deletion of CFHR1/CFHR3 and the presence of CFH antibodies.","date":"2017","source":"Clinical kidney journal","url":"https://pubmed.ncbi.nlm.nih.gov/29225802","citation_count":6,"is_preprint":false},{"pmid":"35617302","id":"PMC_35617302","title":"Copy number variation analysis using next-generation sequencing identifies the CFHR3/CFHR1 deletion in atypical hemolytic uremic syndrome: a case report.","date":"2022","source":"Hematology (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/35617302","citation_count":4,"is_preprint":false},{"pmid":"37147581","id":"PMC_37147581","title":"Atypical haemolytic uremic syndrome with refractory multiorgan involvement and heterozygous CFHR1/CFHR3 gene deletion.","date":"2023","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/37147581","citation_count":2,"is_preprint":false},{"pmid":"39664759","id":"PMC_39664759","title":"Innovative Dual mRNA-Lipid Nanoparticle Therapy Targeting CRHBP and CFHR3 for Enhanced Treatment of Hepatocellular Carcinoma.","date":"2024","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/39664759","citation_count":1,"is_preprint":false},{"pmid":"38524137","id":"PMC_38524137","title":"Case report: A family of atypical hemolytic uremic syndrome involving a CFH::CFHR1 fusion gene and CFHR3-1-4-2 gene duplication.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38524137","citation_count":1,"is_preprint":false},{"pmid":"36070894","id":"PMC_36070894","title":"An Infant Case of Streptococcus Pneumoniae-Associated Thrombotic Microangiopathy with Heterozygous CFI Mutation and CFHR3-CFHR1 Deletion.","date":"2022","source":"The Tohoku journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36070894","citation_count":1,"is_preprint":false},{"pmid":"32038624","id":"PMC_32038624","title":"Corrigendum: High Complement Factor H-Related (FHR)-3 Levels Are Associated With the Atypical Hemolytic-Uremic Syndrome-Risk Allele CFHR3 * B.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32038624","citation_count":0,"is_preprint":false},{"pmid":"42113272","id":"PMC_42113272","title":"Dual pathogenic variants in ADAMTS13 and CFHR1/CFHR3 deletion: divergent thrombotic microangiopathy phenotypes in siblings.","date":"2026","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42113272","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18823,"output_tokens":3335,"usd":0.053247,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10799,"output_tokens":3910,"usd":0.075872,"stage2_stop_reason":"end_turn"},"total_usd":0.129119,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Deletion of CFHR3 and CFHR1 results in absence of both proteins from serum in homozygotes, establishing that these genes encode the serum proteins and that the deletion is a functional null for both.\",\n      \"method\": \"Serum protein detection in homozygous deletion carriers; genomic analysis of deletion haplotype\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein absence confirmed in homozygotes, replicated in independent sample, but single lab for the protein measurement\",\n      \"pmids\": [\"16998489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Homozygous deletion of CFHR3 and CFHR1 impairs protection of erythrocytes from complement activation, as demonstrated in serum of aHUS patients deficient in both proteins, suggesting a regulatory role for CFHR1 and CFHR3 in complement activation.\",\n      \"method\": \"Functional complement activation assay on erythrocytes using patient serum from CFHR1/CFHR3-deficient individuals\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay in patient serum, two independent cohorts, but results conflate CFHR1 and CFHR3 without isolating individual protein contributions\",\n      \"pmids\": [\"17367211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The genomic region encoding CFHR3 and CFHR1 is flanked by long homologous repeats (containing LINEs/retrotransposons), and nonallelic homologous recombination between these repeats leads to an ~84 kb deletion removing both genes.\",\n      \"method\": \"Genomic sequencing and amplification analysis of deletion breakpoints in affected individuals\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — sequence-level characterization of deletion mechanism, single study\",\n      \"pmids\": [\"17367211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A hybrid CFH/CFHR3 gene formed by microhomology-mediated end joining produces a 24-SCR protein that is secreted with normal fluid-phase complement regulatory activity but markedly impaired complement regulation at cell surfaces, despite increased heparin binding, demonstrating that structural integrity of the full factor H molecule is required for cell-surface complement regulation.\",\n      \"method\": \"Genomic characterization of deletion/hybrid gene; functional protein assays (fluid-phase activity, cell-surface regulation, heparin binding) on the hybrid CFH/CFHR3 protein\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — protein biochemistry with multiple orthogonal functional assays (fluid-phase vs. cell-surface activity, heparin binding) on the defined hybrid protein product\",\n      \"pmids\": [\"22058112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FHR-3 binds to C3d and thereby competitively inhibits the interaction between C3d and complement receptor CD21 (CR2), blocking B cell coreceptor complex (CD19/CD21/CD81) colocalization with the BCR. This prevents CD19 and Akt phosphorylation and Ca2+ release, neutralizing the adjuvant effect of C3d on B cell activation.\",\n      \"method\": \"Laser-scanning microscopy and automated image analysis; intracellular phosphorylation assays (CD19, Akt) in Raji cells; Ca2+ release assays in peripheral B cells; competitive binding studies with FHR-3, FHR-1, and factor H\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal functional assays (imaging, phosphorylation, Ca2+ flux) in both cell lines and primary cells, with mechanistic specificity (FHR-3 but not FHR-1 or FH has this effect)\",\n      \"pmids\": [\"27279373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FHR-3 competes with complement factor H (FH) for binding to C3b. A monoclonal antibody (RETC-2) that blocks FHR-3 binding to C3b results in increased FH binding to C3b, establishing a direct competitive relationship between FHR-3 and FH at C3b.\",\n      \"method\": \"Monoclonal antibody generation; binding competition assays between FHR-3 and FH for C3b; immunostaining of human donor retina showing local FHR-3 production by microglia/macrophages\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct competition binding assay with specific mAb modulation, supported by localization data, single lab\",\n      \"pmids\": [\"27965669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FHR-3 serum levels are determined predominantly by CFHR3 gene copy number under normal conditions; the mean FHR-3 concentration (~19 nM) is approximately 132-fold lower than FH in the same samples, and FHR-3 does not behave as a major acute-phase response protein.\",\n      \"method\": \"Specific anti-FHR-3 monoclonal antibodies generated and used in quantitative ELISA; gene copy number variation determined in healthy donors; sepsis cohort acute-phase analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative protein measurement with gene copy number correlation using specific mAbs, single lab, multiple methods within study\",\n      \"pmids\": [\"27007437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The CFHR3*B allele is a high-expression allele associated with increased aHUS risk, producing approximately twofold more FHR-3 protein than the CFHR3*A allele (a low-expression allele), and elevated FHR-3 plasma levels in aHUS patients with the same CFHR3 genotype compared to controls, suggesting that increased FHR-3 alters the FH/FHR-3 balance to impair FH regulatory function.\",\n      \"method\": \"Specific ELISA for FHR-3 quantification in 218 patients with at least one CFHR3 copy; genotyping for CFHR3 alleles (*A, *B, *Del) in controls and aHUS patients\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative protein measurements across genotype groups in large patient cohort, single lab, ELISA method\",\n      \"pmids\": [\"29740447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A hybrid CFHR3-1 gene (formed by gene duplication events at the CFHR3/CFHR1 locus) is associated with complement-mediated glomerulonephritis in an autosomal dominant pattern, and normal copies of both CFHR3 and CFHR1 are present alongside the hybrid gene in affected individuals, linking increased copy number/hybrid gene at this locus to dysregulated complement activation.\",\n      \"method\": \"Copy number analysis across CFHR3 and CFHR1 loci; identification and characterization of hybrid CFHR3-1 gene in affected family members with complement-mediated GN\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic characterization of hybrid gene with disease association, but functional mechanism of the hybrid protein not fully characterized in vitro\",\n      \"pmids\": [\"22626820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A CFHR3 SNP (rs75703017) protects from meningococcal disease by decreasing circulating FH concentrations; mechanistically, deletion of this SNP increases FH expression in hepatocytes by preventing promoter inhibition, as established by dual-luciferase reporter assays and CRISPR gene editing.\",\n      \"method\": \"GWAS sequencing and imputation; dual-luciferase promoter assays; CRISPR gene editing in hepatocytes; FH protein quantification\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — causal variant validated by dual orthogonal experimental approaches (luciferase assay + CRISPR editing) demonstrating promoter-level regulation of FH expression by a CFHR3 intronic SNP\",\n      \"pmids\": [\"36007525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The CFHR3-1 deletion (CFHR3-1Δ) is associated with higher serum CFH levels and lower complement activation (lower C3a), and CFH levels negatively correlate with mesangial C3 deposition in IgAN patients, suggesting that CFHR3 (and CFHR1) modulate complement activation by influencing the FH/FHR balance in vivo.\",\n      \"method\": \"Genotype-phenotype correlation analysis in 1178 IgAN patients; serum CFH, C3, and C3a measurement; linkage analysis of rs6677604-A allele with CFHR3-1Δ\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large cohort genotype-phenotype correlation with complement protein quantification, but observational rather than interventional\",\n      \"pmids\": [\"25205734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of CFHR3 in HCC cells promotes phosphorylation of STAT3 and suppresses p53 expression, promoting cell proliferation, migration, and invasion; miR-590-3p binds the 3'UTR of CFHR3 to downregulate its expression; STAT3 inhibitor (S3I-201) attenuates the malignant phenotypes caused by CFHR3 knockdown.\",\n      \"method\": \"CFHR3 stable knockdown in HCC cells; miR-590-3p 3'UTR binding assay; STAT3 phosphorylation assays; cell proliferation, migration, and invasion assays; STAT3 inhibitor rescue experiment\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple cellular assays with pathway rescue, single lab, mechanism in cancer cell lines may not reflect canonical complement biology\",\n      \"pmids\": [\"35852862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Sequence analysis of 221 kb of human genomic DNA defined the complete exon-intron structure of CFHR3 (fHR-3), established that the majority of SCR-encoding exons follow single-exon/single-SCR architecture with conserved splice phasing, and identified genomic duplications shared between CFH and CFHR3 exons that arose after rodent-primate divergence via retrotransposition and exon duplication.\",\n      \"method\": \"Genomic sequence analysis of PAC clone-derived sequence; RUMMAGE-DP automated annotation; Alu/L1 repeat dating\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/sequence analysis only, no functional protein experiments\",\n      \"pmids\": [\"10781834\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFHR3 encodes a soluble complement regulator (FHR-3) that competes with complement factor H (FH) for binding to C3b and C3d: FHR-3 binds C3d to block CD21-mediated B cell coreceptor activation, competes with FH at C3b to modulate alternative pathway regulation, and its plasma concentration (determined largely by CFHR3 gene copy number and allele type) sets the FH/FHR-3 balance that governs complement activity; a CFHR3 intronic SNP additionally controls FH expression at the transcriptional level in hepatocytes, linking CFHR3 genetic variation to systemic complement regulation and susceptibility to diseases including AMD, aHUS, and IgA nephropathy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CFHR3 encodes FHR-3, a soluble plasma complement regulator that fine-tunes alternative-pathway activity by competing with complement factor H (FH) for shared ligands [#5]. FHR-3 binds C3b and directly competes with FH for this interaction, such that blocking FHR-3 binding increases FH occupancy at C3b, positioning FHR-3 as a modulator of the FH/FHR-3 balance that governs complement regulation [#5]. FHR-3 also binds C3d and competitively displaces it from complement receptor CD21 (CR2), preventing assembly of the CD19/CD21/CD81 B cell coreceptor with the BCR and thereby blocking CD19 and Akt phosphorylation and Ca2+ flux \\u2014 an effect specific to FHR-3 and not shared by FHR-1 or FH \\u2014 which neutralizes the C3d adjuvant signal on B cells [#4]. FHR-3 plasma concentration is set predominantly by CFHR3 gene copy number and allele type, with a high-expression CFHR3*B allele producing roughly twofold more protein and associating with aHUS risk by shifting the FH/FHR-3 balance to impair FH regulation [#6, #7]. Beyond its protein product, the CFHR3 locus controls FH itself: an intronic SNP (rs75703017) regulates FH expression at the transcriptional level in hepatocytes through promoter inhibition, so that deletion of the SNP raises FH and protects from meningococcal disease [#9]. Genomic instability at the locus \\u2014 driven by flanking homologous repeats \\u2014 generates a common CFHR3/CFHR1 deletion that removes both proteins from serum and impairs protection of erythrocytes from complement activation, and also produces hybrid genes associated with complement-mediated glomerulonephritis [#0, #1, #2, #8]. Through these genetic and protein-level mechanisms, CFHR3 variation is linked to aHUS, IgA nephropathy, and complement-mediated glomerulonephritis [#7, #8, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Before any functional work, the gene architecture had to be defined; sequencing the locus established the exon-intron and SCR-module organization of CFHR3 and revealed its evolutionary origin from CFH-related duplications.\",\n      \"evidence\": \"Genomic sequence analysis of PAC clones with automated annotation and repeat dating\",\n      \"pmids\": [\"10781834\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational/sequence analysis only, no functional protein data\", \"Does not establish the protein's biochemical activity or ligands\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"It was unknown whether the CFHR3/CFHR1 genes encode detectable serum proteins; demonstrating their complete absence in homozygous deletion carriers established the genes as functional and defined a natural null.\",\n      \"evidence\": \"Serum protein detection in homozygous deletion carriers with genomic analysis of the deletion haplotype\",\n      \"pmids\": [\"16998489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not isolate FHR-3 from FHR-1 contributions\", \"No molecular function assigned to either protein\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The physiological consequence of losing these proteins was unclear; patient serum lacking both showed impaired protection of erythrocytes from complement, implicating CFHR3/CFHR1 in complement regulation.\",\n      \"evidence\": \"Functional complement activation assay on erythrocytes using serum from CFHR1/CFHR3-deficient aHUS patients\",\n      \"pmids\": [\"17367211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conflates CFHR1 and CFHR3 without isolating individual contributions\", \"Patient serum context confounds with disease background\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The basis for the recurrent deletion was undefined; breakpoint sequencing showed it arises by nonallelic homologous recombination between flanking repeats, explaining the locus's genomic instability.\",\n      \"evidence\": \"Genomic sequencing and amplification analysis of deletion breakpoints\",\n      \"pmids\": [\"17367211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Does not address functional consequences of the deletion at protein level\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"To dissect what structural features control surface complement regulation, a CFH/CFHR3 hybrid protein was characterized, showing retained fluid-phase activity but lost cell-surface regulation, establishing that full FH structural integrity is required for surface control.\",\n      \"evidence\": \"Genomic characterization plus orthogonal functional assays (fluid-phase activity, cell-surface regulation, heparin binding) on the hybrid protein\",\n      \"pmids\": [\"22058112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Concerns a hybrid product rather than native FHR-3\", \"Does not define native FHR-3 ligand specificity\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether locus rearrangements beyond deletion cause disease was open; a hybrid CFHR3-1 gene present alongside normal gene copies was found in autosomal dominant complement-mediated glomerulonephritis, linking increased copy/hybrid gene to complement dysregulation.\",\n      \"evidence\": \"Copy number analysis and hybrid gene characterization in an affected family\",\n      \"pmids\": [\"22626820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional mechanism of the hybrid protein not characterized in vitro\", \"Single family\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The in vivo direction of the FH/FHR balance effect was unproven; in IgAN patients the CFHR3-1 deletion correlated with higher serum FH, lower C3a, and reduced mesangial C3 deposition, indicating CFHR3 modulates complement activation by shifting this balance.\",\n      \"evidence\": \"Genotype-phenotype correlation in 1178 IgAN patients with serum CFH/C3/C3a measurement\",\n      \"pmids\": [\"25205734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Observational, not interventional\", \"Cannot separate CFHR3 from CFHR1 in the deletion\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"FHR-3's molecular targets and a B-cell function were undefined; FHR-3 was shown to bind C3d and block C3d-CD21 interaction, preventing B cell coreceptor assembly and signaling, and to compete with FH at C3b, defining its dual ligand engagement.\",\n      \"evidence\": \"Imaging, phosphorylation and Ca2+ flux assays in B cells; competition binding assays with a blocking mAb; retinal localization\",\n      \"pmids\": [\"27279373\", \"27965669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each ligand interaction in vivo not resolved\", \"C3b competition shown biochemically without surface-regulation outcome\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The determinants of circulating FHR-3 were unknown; quantitative ELISA showed serum FHR-3 is set mainly by gene copy number, is ~132-fold lower than FH, and is not a major acute-phase protein.\",\n      \"evidence\": \"Specific anti-FHR-3 mAb ELISA with gene copy number determination and sepsis cohort analysis\",\n      \"pmids\": [\"27007437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab quantification\", \"Does not link concentration directly to a functional outcome\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether allelic expression differences drive disease risk was open; the high-expression CFHR3*B allele produced ~twofold more FHR-3 and associated with elevated FHR-3 and aHUS risk, supporting a dosage-dependent impairment of FH regulation.\",\n      \"evidence\": \"FHR-3 ELISA across CFHR3 genotypes in 218 patients with allele genotyping in controls and aHUS\",\n      \"pmids\": [\"29740447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between elevated FHR-3 and impaired FH function inferred, not directly demonstrated\", \"Single ELISA platform\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The locus's influence on FH itself was unexplained; an intronic CFHR3 SNP was shown to regulate hepatocyte FH expression via promoter inhibition, with SNP deletion raising FH and protecting from meningococcal disease.\",\n      \"evidence\": \"GWAS imputation, dual-luciferase promoter assays, and CRISPR editing in hepatocytes with FH quantification\",\n      \"pmids\": [\"36007525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Defines a transcriptional mechanism distinct from FHR-3 protein function\", \"Does not address tissues beyond hepatocytes\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A non-complement role was probed in cancer; CFHR3 knockdown in HCC cells activated STAT3 and suppressed p53 to promote proliferation/migration/invasion, with miR-590-3p targeting its 3'UTR and a STAT3 inhibitor rescuing the phenotype.\",\n      \"evidence\": \"Stable knockdown, 3'UTR binding assay, STAT3 phosphorylation, migration/invasion and inhibitor rescue assays in HCC cell lines\",\n      \"pmids\": [\"35852862\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab in cancer cell lines, may not reflect complement biology\", \"No in vivo validation of the STAT3/p53 axis\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competing roles of FHR-3 protein (C3b/C3d competition) and CFHR3-locus transcriptional control of FH integrate quantitatively to set net complement activity in specific tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling protein-level competition with locus-level FH regulation\", \"Tissue-specific contributions of FHR-3 vs FH not quantified\", \"Structural basis of FHR-3 ligand binding not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"C3b\", \"C3d\", \"CFH\", \"CD21\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}