Other entities represented in this entry:
HGNC Approved Gene Symbol: C3
SNOMEDCT: 771443008;
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:6,677,704-6,720,650 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | {Hemolytic uremic syndrome, atypical, susceptibility to, 5} | 612925 | Autosomal dominant | 3 |
| {Macular degeneration, age-related, 9} | 611378 | 3 | ||
| C3 deficiency | 613779 | Autosomal recessive | 3 |
The complement system is an important mediator of natural and acquired immunity. It consists of approximately 30 proteins that can exhibit catalytic activity, function as regulators, or act as cellular surface receptors. These components normally circulate in inactive forms and are activated by the classical, alternative, or lectin pathways. Complement component 3 plays a central role in all 3 activation pathways (summary by Reis et al., 2006).
For a review of the complement system and its components, see Degn et al. (2011).
De Bruijn and Fey (1985) presented the complete coding sequence of the C3 gene and the derived amino acid sequence. C3 is an acute phase reactant; increased synthesis of C3 is induced during acute inflammation. The liver is the main site of synthesis, although small amounts are also produced by activated monocytes and macrophages. A single chain precursor (pro-C3) of approximately 200 kD is found intracellularly; the cDNA shows that it comprises 1,663 amino acids. This is processed by proteolytic cleavage into alpha (C3a) and beta (C3b) subunits which in the mature protein are linked by disulfide bonds. Pro-C3 contains a signal peptide of 22 amino acid residues, the beta chain (645 residues) and the alpha chain (992 residues). The 2 chains are joined by 4 arginine residues that are not present in the mature protein. Human C3 has 79% identity to mouse C3 at the nucleotide level and 77% at the amino acid level.
Crystal Structure
Janssen et al. (2005) presented the crystal structures of native C3 and its final major proteolytic fragment C3c. The structures revealed 13 domains, 9 of which were unpredicted, and suggested that the proteins of the alpha-2-macroglobulin family evolved from a core of 8 homologous domains. A double mechanism prevents hydrolysis of the thioester group, essential for covalent attachment of activated C3 to target surfaces. Marked conformational changes in the alpha chain, including movement of a critical interaction site through a ring formed by the domains of the beta chain, indicated an unprecedented, conformation-dependent mechanism of activation, regulation, and biologic function of C3.
Janssen et al. (2006) presented the crystal structure at 4-angstrom resolution of the activated complement protein C3b and described the conformation rearrangements of the 12 domains that take place upon proteolytic activation. In the activated form the thioester is fully exposed for covalent attachment to target surfaces and is more than 85 angstroms away from the buried site in native C3. Marked domain rearrangements in the alpha chain present an altered molecular surface, exposing hidden and cryptic sites that are consistent with known putative binding sites of factor B (CFB; 138470) and several complement regulators. The structural data indicated that the large conformational changes in the proteolytic activation and regulation of C3 take place mainly in the first conversion step, from C3 to C3b.
Wiesmann et al. (2006) presented the crystal structure of C3b in complex with CRIG (300353) and, using CRIG mutants, provided evidence that CRIG acts as an inhibitor of the alternative pathway of complement. The structure shows that activation of C3 induces major structural rearrangements, including a dramatic movement (greater than 80 angstroms) of the thioester bond-containing domain through which C3b attaches to pathogen surfaces. Wiesmann et al. (2006) showed that CRIG is not only a phagocytic receptor, but also a potent inhibitor of the alternative pathway convertases. Wiesmann et al. (2006) concluded that the structure provides insights into the complex macromolecular structural rearrangements that occur during complement activation and inhibition.
Forneris et al. (2010) presented crystal structures of the proconvertase C3bB at 4-angstrom resolution and its complex with factor D at 3.5-angstrom resolution. Their data showed how factor B binding to C3b forms an open 'activation' state of C3bB. Factor D specifically binds the open conformation of factor B through a site distant from the catalytic center and is activated by the substrate, which displaces factor D's self-inhibitory loop. This concerted proteolytic mechanism, which if cofactor-dependent and substrate-induced, restricts complement amplification to C3b-tagged target cells.
The report of Ajees et al. (2006) that presented a structure of C3b was retracted by the journal Nature.
Component C3 plays several important biologic roles in the classical, alternative, and lectin activation pathways, e.g., (1) formation of C3- and C5-convertases, both essential for the full activation of the system; (2) production of opsonins that enhance phagocytosis of microorganisms; (3) degranulation of mast cells and basophils medicated by the fragments C3a and C5a; (4) solubilization and clearance of C3b-bound immune complexes; (5) adjuvant function of fragments C3d and C3dg; and (6) clearance of apoptotic cells (summary by Reis et al., 2006).
Polymorphisms in complement factor H (CFH; 134370), the main regulator of the activation of C3, have been associated with susceptibility to age-related macular degeneration (see ARMD4, 610698). Sivaprasad et al. (2007) noted that only the C3a des Arg form of C3a is present in human plasma. They therefore studied the levels of C3a des Arg in 84 persons with a clinical diagnosis of ARMD compared with those in age-matched controls. The levels were significantly raised in the patient group compared with those in the control group. Sivaprasad et al. (2007) also found that the concentration of plasma C3a des Arg did not differ significantly between those with different CFH genotypes. The authors suggested that systemic activation of the complement system may contribute to the pathogenesis of ARMD independent of CFH polymorphism.
By immunofluorescence microscopy, Rahpeymai et al. (2006) demonstrated that mouse neural progenitor cells and immature neurons expressed C3ar (605246) and C5ar (113995). Mice lacking C3 or C3ar, or treated with a C3ar antagonist, show decreased basal neurogenesis and impaired ischemia-induced neurogenesis in the subventricular zone and in the ischemic region. Rahpeymai et al. (2006) concluded that, in the adult mammalian CNS, complement activation products promote both basal and ischemia-induced neurogenesis.
Using proteomic analysis on human psoriatic epidermis (see 177900), Schonthaler et al. (2013) identified S100A8 (123885) and S100A9 (123886), followed by C3, as the most upregulated proteins specifically expressed in lesional psoriatic skin. Confocal microscopy of human primary keratinocytes treated with TPA (PLAT; 173370) demonstrated a strong increase in nuclear as opposed to cytoplasmic expression of S100A9. Schonthaler et al. (2013) deleted S100a9 in the Jun (165160)/JunB (165161) double-knockout (DKO) mouse model of psoriasis and observed an absence of scaly plaques on the ears and tails, as well as decreased amounts of C3. Inhibition of C3 in DKO mice also strongly reduced inflammatory skin disease. Chromatin immunoprecipitation analysis using DKO cells and S100a9 DKO -/- cells as controls demonstrated binding of S100a9 to the C3 promoter region. Chromatin immunoprecipitation analysis on human keratinocytes also suggested binding of S100A9 to the C3 promoter. Schonthaler et al. (2013) concluded that S100A8/S100A9 regulates C3 at the nuclear level.
Nan et al. (2013) noted that the subretinal pigment epithelial deposits that are a hallmark of age-related macular degeneration contain both C3b and millimolar levels of zinc. By ultracentrifugation and x-ray scattering, they showed that of C3, C3u, and C3b associated strongly with a zinc concentration over 100 micromol, whereas C3c and C3d associated only weakly. In the presence of zinc, C3 formed soluble oligomers, whereas C3u and C3b precipitated. CFH formed large oligomers with a zinc concentration over 10 micromol. The complex of CFH and C3b lost solubility and was precipitated by zinc in a concentration-dependent manner, thereby inhibiting complement activation. Nan et al. (2013) concluded that zinc-induced precipitation may contribute to the initial development of subretinal pigment epithelial deposits in retina and reduce progression to advanced age-related macular degeneration in higher risk patients.
Using mouse models, Hong et al. (2016) showed that complement and microglia mediate synaptic loss early in Alzheimer disease (AD; 104300). C1q (see 120550), the initiating protein of the classical complement cascade, was increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3, or the microglial complement receptor CR3 (CD11b/CD18; see 600065) reduced the number of phagocytic microglia, as well as the extent of early synapse loss. C1q was necessary for the toxic effects of soluble beta-amyloid (A-beta; 104760) oligomers on synapses and hippocampal long-term potentiation. Finally, microglia in adult brains engulfed synaptic material in a CR3-dependent process when exposed to soluble A-beta oligomers. Together, these findings suggested that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.
Fong et al. (1990) reported that the complete C3 gene is 41 kb long, comprising 41 exons. The beta chain spans 13 kb from exon 1 to exon 16. Exon 16 encodes both alpha and beta chains. The alpha chain is 28 kb long, with 26 exons, including exon 16.
Weitkamp et al. (1974) presented evidence that the Lewis blood group locus and the C3 locus are linked. Three independent studies, by Ott et al. (1974), Berg and Heiberg (1976) and Elston et al. (1976), strongly suggested loose linkage between familial hypercholesterolemia and C3.
By the method of somatic cell hybridization, Whitehead et al. (1982) assigned the gene for fibroblast-derived C3 to chromosome 19. It was at first unclear whether fibroblast and serum C3 were identical; it was known that fibroblast C1q (120560) and serum C1q (120550) are different (Skok et al., 1981). Studies with a C3 probe (Davies et al., 1984) suggested that there was only one C3 gene per haploid chromosome set; no other hybridization was observed with relaxed stringency. Furthermore, no recombination was observed between probe and serum C3 (Williamson, 1983). Thus, serum and fibroblast C3 almost certainly have the same genetic basis. A specific antihuman C3 monoclonal antibody was used by Whitehead et al. (1982) in their mapping studies. The assignment to chromosome 19 was confirmed by use of a unique-sequence human genomic C3 DNA clone as a probe in DNA hybridization experiments with DNA prepared from appropriate human-mouse somatic cell hybrids (Whitehead et al., 1982).
Sanders et al. (1984) studied the linkage of polymorphic serum C3 to Lewis (618983) and secretor (182100) and found low positive lod scores for all 3 linkages. They favored the order SE--C3--LE. Eiberg et al. (1983) found linkage of secretor with the serum C3 polymorphism (male lod = 4.35, theta = 0.12). There was suggestive evidence of linkage of secretor with PEPD (male and female lod = 2.41, theta = 0.00) and of C3 with PEPD (male lod = 0.95, theta = 0.17)--independent confirmation of assignment to chromosome 19 where PEPD is known to be by somatic cell studies. What they termed Lewis secretion (LES) was also linked to C3 (male lod = 3.63, theta = 0.04). They suggested that the most likely sequence is LES--C3--DM--(Se-PEPD)--Lu.
Ball et al. (1984) regionalized C3 to 19pter-p13.2. Brook et al. (1984) assigned the gene to 19pter-p13 and concluded that familial hypercholesterolemia is probably distal to C3 in the pter-p13 segment. Brook et al. (1985) later presented data suggesting that the LDL receptor is proximal to C3.
Lusis et al. (1986) used a reciprocal whole arm translocation between the long arm of 19 and the short arm of chromosome 1 to map APOC1, APOC2, APOE, and GPI to the long arm and LDLR, C3, and PEPD to the short arm. Furthermore, they isolated a single lambda phage that carried both APOC1 and APOE separated by about 6 kb of genomic DNA. Since family studies indicate close linkage of APOE and APOC2, the 3 must be in a cluster on 19q. Judging by the sequence of loci suggested by linkage data (pter--FHC--C3--APOE/APOC2), the location of LDLR is probably 19p13.2-p13.12 and of C3, 19p13.2-p13.11.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
In a grandmother, mother, and 2 sons, Wieme and Demeulenaere (1967) found a double electrophoretic band corresponding apparently to complement component C-prime-3 (as it was then called). By means of high voltage starch gel electrophoresis, Azen and Smithies (1968) also found electrophoretic polymorphism of the third component of complement. This component has many important functions in immune mechanisms. Alper and Propp (1968) independently found polymorphism of C3.
Complement Component 3 Deficiency
Alper et al. (1972) described an Afrikaner patient with a striking susceptibility to pyogenic infection who was apparently homozygous for C3 deficiency (613779). Her C3 levels were one-thousandth or less of normal. Many relatives, including both parents, had approximately half-normal levels. In the patient reported by Alper et al. (1972), Botto et al. (1992) demonstrated homozygosity for a partial deletion of the C3 gene (120700.0004) as the molecular basis of the deficiency.
Nilsson et al. (1992) described 3 sisters who were compound heterozygotes for a null allele inherited from the father and a dysfunctional C3 allele inherited from the mother. Alternative pathway complement function was absent, but classic pathway complement function was partially intact. One of the sisters, the proband, had an SLE-like disease. The proband's C3 proved normally susceptible to trypsin proteolysis and partially resistant to classical pathways, but completely resistant to alternative pathway, convertase-dependent cleavage.
In a 22-year-old Japanese male patient with C3 deficiency and an SLE-like, who was born of consanguineous parents, Tsukamoto et al. (2005) identified a homozygous splice site mutation (120700.0009).
Age-Related Macular Degeneration
Yates et al. (2007) genotyped SNPs spanning the complement genes C3 and C5 in 603 Caucasian English patients with age-related macular degeneration (ARMD9; 611378) and 350 controls and found that the common functional R102G polymorphism in the C3 gene (rs2230199; 120700.0001), was strongly associated with ARMD (p = 5.9 x 10(-5)). The association was replicated in a Scottish group of 244 cases and 351 controls (p = 5.0 x 10(-5)).
Maller et al. (2007) identified a nonsynonymous coding change in C3 that was strongly associated with risk of age-related macular degeneration in a large case-control sample (p less than 10(-12)). The nonsynonymous coding change (R102G) in the third exon of C3 was the same as that identified by Yates et al. (2007).
Seddon et al. (2013) sequenced the exons of 681 genes within all reported ARMD loci and related pathways in 2,493 cases. Seddon et al. (2013) genotyped 5,115 independent samples and confirmed associations with ARMD of an allele in C3 encoding a lys155-to-gln variant (120700.0010).
Susceptibility to Atypical Hemolytic Uremic Syndrome 5
In 11 probands with atypical hemolytic uremic syndrome (AHUS5; 612925), Fremeaux-Bacchi et al. (2008) identified 9 different mutations in the C3 gene (see, e.g., 120700.0005-120700.0008). Five of the mutations resulted in a gain of function with resistance to degradation by MCP (120920) and CFI (217030), and 2 resulted in haploinsufficiency. Family history, when available, showed decreased penetrance.
Because C3, C4 (120810), and C5 (120900) are strikingly similar, a common evolutionary origin has been supposed (Whitehead et al., 1982). C4 is in the major histocompatibility complex on chromosome 6, but C3 and C5 are not. (In the mouse, both C3 and H2 are on chromosome 17, but not in close proximity. In the chimpanzee, as in man, C2 (613927) and Bf are closely linked to the MHC and neither C3 nor C8 (120950) is closely linked to MHC. C6 deficiency was observed in the chimpanzee.) The protease alpha-2-macroglobulin (103950) also shows considerable homology to C3, suggesting a common evolutionary origin.
Johnson et al. (1986) described C3 deficiency in Brittany spaniel dogs. Like the human disorder, this appears to be due to a null gene which apparently is not closely linked to the canine major histocompatibility complex.
Circolo et al. (1999) generated C3-deficient mice by disrupting the promoter region and exon 1 of the C3 gene. They detected C3 expression in lung, kidney, heart, spleen, and adipose, but not liver tissue, in these mice. Although pro-C3 could be found in lung tissue, there was no detectable secretion of mature C3. The mutant mice had dramatically decreased resistance to S. pneumoniae. Circolo et al. (1999) concluded that this model could be useful for the study of complete C3 deficiency.
Functional impairment of ASP has been hypothesized to be a major cause of hyperapobetalipoproteinemia. However, Wetsel et al. (1999) could not detect significant differences in lipids or lipoproteins in sera of Asp-deficient mice and wildtype mice. They concluded that Asp deficiency does not cause hyperapobetalipoproteinemia in mice.
Using C3-deficient mice in an allergen-induced model of pulmonary allergy, Drouin et al. (2001) showed that these mice had diminished airway hyperresponsiveness and lung eosinophilia. ELISPOT analysis demonstrated reduced numbers of interleukin-4 (IL4; 147780)-producing cells and attenuated antigen-specific IgE and IgG responses. Drouin et al. (2001) concluded that C3 contributes significantly to the pathogenesis of asthma resulting from pulmonary allergy and that complement has a role in the production of IL4, a Th2 cytokine that is critical to the development of airway hyperresponsiveness and IgE responses in asthma.
Pratt et al. (2002) noted that the role of local, as opposed to hepatic, secretion of complement by epithelial and vascular cells is unclear. Proximal tubular epithelial cells (PTECs) synthesize C3 in transplanted kidneys and production by PTECs increases during transplant rejection. Pratt et al. (2002) found that in mice, wildtype-donor transplanted kidneys were rejected by recipients in 12 days, whereas C3 -/- donor kidneys transplanted into immunocompetent recipients survived for over 100 days. When C3-deficient mice were the recipients, the grafts survived only 16 days, suggesting that locally synthesized rather than circulating C3 has a greater influence on graft rejection. RT-PCR and immunohistochemical analysis indicated that the cortical tubular epithelium is the principal site of C3 expression as well as being the main site of graft inflammation. Stimulation ex vivo of T cells from recipients of C3-null kidneys generated reduced responses in mixed lymphocyte reactions. Interferon-gamma (IFNG; 147570) treatment of wildtype PTECs enhanced C3 production, but the expression of CD80 (112203), CD86 (601020), or MHC class II was not different in treated C3-deficient cells. IL2 (147680) production was also lower in response to Ifng-treated PTECs from C3 -/- mice. Flow cytometric analysis demonstrated an expanded population of CD4+ Th1-like cells expressing complement receptors CR1 (120620) and CR2 (120650) in the spleens of the recipients of wildtype kidneys. Immunofluorescence microscopy demonstrated rejecting graft infiltrates containing a similar population of T cells in the peritubular and perivascular regions. Pratt et al. (2002) concluded that local tissue production of C3 is important in renal graft survival and that rejection is most likely mediated by T cell recognition of C3-tagged graft cells.
Acylation-stimulating protein (ASP) is an adipocyte-derived product of C3 cleavage and modification. ASP acts as a paracrine anabolic regulator toward adipose tissue by stimulating glucose uptake and nonesterified fatty acid storage. Genetic deficiency of C3 in mice leads to reduced body fat and decreased leptin (164160) levels. Some male mice also show delayed triglyceride clearance. Xia et al. (2002) developed C3 and leptin (ob/ob) double-knockout (2KO) mice. Compared with ob/ob mice, 2KO mice had delayed postprandial triglyceride and fatty acid clearance that was associated with decreased body weight and increased insulin sensitivity. Food intake was increased over that of ob/ob mice, but this was balanced by increased energy expenditure as measured by oxygen consumption. Although several metabolic measures were improved relative to ob/ob mice, they were not returned to normal. Xia et al. (2002) concluded that the regulation of energy storage by ASP influences energy expenditure and metabolic balance.
Huber-Lang et al. (2006) found that wildtype mice and C3 -/- mice developed intense lung injury after immune complex deposition, whereas injury was attenuated in C5 (120900) -/- mice. Wildtype and C3 -/- mice had similar levels of C5a in bronchoalveolar lavage fluid, and lung injury was attenuated by administration of anti-C5a. Treatment of C3 -/- mice, but not wildtype mice, with antithrombin or the leech anticoagulant hirudin also attenuated lung injury. C3 -/- mice had 3-fold more thrombin (F2; 176930) activity than wildtype mice, and levels of prothrombin mRNA and protein and thrombin protein in liver were higher than in wildtype mice. Incubation of human C5 with thrombin generated biologically active C5a. Huber-Lang et al. (2006) concluded that, in the absence of C3, thrombin substitutes for C3-dependent C5 convertase and that there is linkage between the complement and coagulation pathways to activate complement.
Using a mouse model of West Nile virus (WNV; see 610379) neuroinvasive disease, Vasek et al. (2016) showed that viral infection of adult hippocampal neurons induced complement-mediated elimination of presynaptic terminals. In contrast with models using virulent WNV strains, infection of mice with a WNV strain with a mutation in nonstructural protein-5 (NS5) resulted in survival rates and cognitive dysfunction similar to those observed in human WNV neuroinvasive disease. Recovered mice displayed impaired spatial learning and persistence of phagocytic microglia without loss of hippocampal neurons or volume. Hippocampi from recovered mice with poor spatial learning showed increased expression of genes that drive synaptic remodeling by microglia via complement. During WNV neuroinvasive disease, C1qa was upregulated and localized to microglia. Mice with fewer microglia, i.e. Il34 (612081) -/- mice, or with deficiency of C3 or C3ar were protected from WNV-induced synaptic terminal loss. Vasek et al. (2016) proposed that C3 and C3ar mediate presynaptic terminal loss in hippocampi of mice exhibiting spatial learning defects during recovery from WNV neuroinvasive disease.
Botto et al. (1990) studied the molecular basis of the C3F versus C3S polymorphism. The less common variant, C3F, occurs with appreciable frequencies (gene frequency = 0.20) only in the Caucasoid populations. Botto et al. (1990) found a single-nucleotide change, C to G, at position 364 in exon 3, distinguishing C3S and C3F. This led to a substitution of an arginine residue in C3S for a glycine residue in C3F (R102G). The substitution resulted in a polymorphic restriction site for the enzyme HhaI.
The 3 pathways of complement activation proceed through the cleavage of C3, the most abundant and functionally diverse complement component. The renal tubular epithelium is both an important extrahepatic source of C3 and a major target of immunologic injury during rejection of renal grafts. The donor kidney contributes 5% of the total circulating C3 pool when it is in its stable state but up to 16% during acute rejection. Brown et al. (2006) determined the C3 allotypes of 662 pairs of adult kidney donors and recipients and then related C3F/S polymorphism status to demographic and clinical outcome data. Among white C3S/S recipients, receipt of a C3F/F or C3F/S donor kidney, rather than a C3S/S donor kidney, was associated with a significantly better long-term outcome. These findings suggested that the 2 alleles have functional differences.
In a study of 603 Caucasian English patients with age-related macular degeneration (ARMD9; 611378) and 350 controls, Yates et al. (2007) found that the R102G polymorphism, which they referred to as R80G based on numbering that eliminated the 22 residues of the signal peptide, was strongly associated with ARMD (p = 5.9 x 10(-5)). The association was replicated in a Scottish group of 244 cases and 351 controls (p = 5.0 x 10(-5)). The 102R and 102G alleles correspond to slow (C3S) and fast (C3F) electrophoretic variants, respectively. The odds ratio for ARMD in SF heterozygotes and FF homozygotes was 1.7 and 2.6, respectively, compared to SS homozygotes. The estimated population attributable risk for C3F was 22%.
Maller et al. (2007) also found association of ARMD with R102G in a large case-control sample (P less than 10(-12)).
In a matched sample set from the Age-Related Eye Disease Study (AREDS) cohort involving 424 patients with ARMD and 215 patients without ARMD acting as controls, Bergeron-Sawitzke et al. (2009) confirmed association between ARMD and rs2230199, with both the CG (OR, 1.9; p = 9.0 x 10(-4)) and GG (OR, 2.5; p = 0.03) genotypes.
Fritsche et al. (2013) identified association of the C allele of rs2230199 with increased risk of ARMD (OR 1.42, 95% CI 1.37-1.47, combined p = 1 x 10(-41)).
Botto et al. (1990) identified the molecular basis of a structural polymorphism of C3, identified by the monoclonal antibody HAV 4-1: codon 314 in exon 9 of the beta chain showed a change of a proline residue in the HAV 4-1(-) form to a leucine residue in the HAV 4-1(+) form.
Botto et al. (1990) studied the DNA from a 10-year-old boy who had suffered from recurrent attacks of otitis media during the first 3 years of life. Between 5 and 8 years of age, he suffered from more than 20 episodes of rash which affected his face, forearms, and hands and resembled the target lesions of erythema multiforme. Attacks were normally preceded by an upper respiratory infection, and a group A beta-hemolytic Streptococcus was isolated from his throat during 2 episodes. The parents were consanguineous ('share a common great-grandparent'). C3 could not be detected by RIA of serum from the patient (613779). Segregation of C3S and C3F allotypes within the family confirmed the presence of a null allele, for which the patient was homozygous. DNA studies showed a GT-to-AT mutation at the 5-prime donor splice site of intron 18 of the C3 gene. Exons 17-21 were amplified by PCR from first-strand cDNA synthesized from mRNA obtained from peripheral blood monocytes. This revealed a 61-bp deletion in exon 18, resulting from splicing of a cryptic 5-prime donor splice site in exon 18 with the normal 3-prime splice site in exon 19. The deletion led to a disturbance of the reading frame of the mRNA with a stop codon 17 bp downstream from the abnormal splice in exon 18. Both parents were heterozygous for the C3*Q0 allele (Q0 = quantity zero, i.e., null allele).
Botto et al. (1992) demonstrated partial gene deletion as the molecular basis of C3 deficiency (613779) in an Afrikaner patient previously described by Alper et al. (1972) as homozygous C3 deficient. By Southern blot analysis, they demonstrated that the C3 null gene had an 800-bp deletion in exons 22 and 23, resulting in a frameshift and a stop codon 19 bp downstream from the deletion. DNA sequence analysis showed that the deletion probably arose from homologous recombination between 2 ALU repeats flanking the deletion. This mutant allele was found to have a gene frequency of 0.0057 in the South African Afrikaans-speaking population.
In 2 sibs with atypical hemolytic uremic syndrome (AHUS5; 612925), Fremeaux-Bacchi et al. (2008) identified a heterozygous 1775G-A transition in exon 14 of the C3 gene, resulting in an arg570-to-gln (R570Q) substitution. Both patients developed end-stage renal disease and had a total of 5 renal transplants; disease recurred in 1 of the patients after transplant. In vitro functional expression studies showed that binding of the mutant C3 protein to MCP (120290) was decreased to 22% of wildtype, which would result in resistance to cleavage by factor I (CFI; 217030). The mutant C3 also showed reduced binding to factor H (CFH; 134370) and iC3. The findings indicated that a modification in interactions with regulators results in a secondary gain of function of mutant C3. A third unrelated patient also carried this mutation, which was inherited from her unaffected mother.
In a 2-year-old girl with atypical hemolytic uremic syndrome-5 (612925), Fremeaux-Bacchi et al. (2008) identified a heterozygous 3281C-T transition in exon 26 of the C3 gene, resulting in an ala1072-to-val (A1072V) substitution. She recovered by age 15 years. Her unaffected father also carried the mutation. In vitro functional expression studies showed that binding of the mutant C3 protein to MCP (120290) was decreased to 18% of wildtype, which would result in resistance to cleavage by factor I (CFI; 217030). The mutant C3 also showed reduced binding to factor H (CFH; 134370) and iC3. The findings indicated that a modification in interactions with regulators results in a secondary gain of function of mutant C3.
In a 23-year-old woman with atypical hemolytic uremic syndrome (AHUS5; 612925), Fremeaux-Bacchi et al. (2008) identified a heterozygous 3343G-A transition in exon 26 of the C3 gene, resulting in an asp1093-to-asn (D1093N) substitution. She had end-stage renal disease and 2 kidney transplants. In vitro functional expression studies showed that binding of the mutant C3 protein to MCP (120290) was decreased to 17% of wildtype, which would result in resistance to cleavage by factor I (CFI; 217030). The mutant C3 also showed reduced binding to factor H (CFH; 134370) and iC3. The findings indicated that a modification in interactions with regulators results in a secondary gain of function of mutant C3.
In a 6-year-old boy with atypical hemolytic uremic syndrome-5 (612925), Fremeaux-Bacchi et al. (2008) identified a heterozygous 2562C-G transversion in exon 20 of the C3 gene, resulting in a tyr832-to-ter (Y832X) substitution. The patient recovered by age 10 years. His unaffected mother also carried the mutation. The mutation was predicted to result in haploinsufficiency of C3. The authors noted that this finding made the pathogenic mechanism difficult to explain relative to the concept of increased complement activation as the predisposing event in aHUS.
In a 22-year-old Japanese male patient with C3 deficiency (613779) and systemic lupus erythematosus, born of consanguineous parents, Tsukamoto et al. (2005) identified a homozygous A-to-G transition in the acceptor site of intron 38 of the C3 gene, resulting in skipping of exon 39. Complement assay detected no C3 in serum and only a trace amount of C3 hemolytic activity. Both parents and 2 sibs were heterozygous for the mutation, and all had reduced levels of C3 hemolytic activity. The patient had suffered from photosensitivity, recurrent fever, and facial erythema from childhood. Expression of the mutant cDNA in COS-7 cells resulted retention of the molecule in the ER-Golgi intermediate compartment due to defective secretion. Tsukamoto et al. (2005) concluded that SLE or an SLE-like disease is a complication of hereditary homozygous C3 deficiency in Japan.
Seddon et al. (2013) identified an increased risk of age-related macular degeneration (ARMD9; 611378) in individuals with a lys155-to-gln (K155Q) variant (rs147859257) with a joint p value of 5.2 x 10(-9) and an odds ratio of 3.8. Seddon et al. (2013) showed that substitution of gln for lys at codon 155 results in resistance to proteolytic inactivation by CFH (134370) and CFI (217030). They concluded that their results implicated loss of C3 protein regulation and excessive alternative complement activation in ARMD pathogenesis.
Through whole-genome sequencing of 2,230 Icelanders, Helgason et al. (2013) detected a rare nonsynonymous SNP with a minor allele frequency of 0.55% in the C3 gene encoding a K155Q substitution which, following imputation into a set of Icelandic cases with ARMD and controls, associated with disease (odds ratio = 3.45; p = 1.1 x 10(-7)). This signal was independent of the common SNPs in C3 encoding P314L (120700.0002) and R102G (120700.0001) that associate with ARMD. The association of the K155Q variant was replicated in ARMD case-control samples of European ancestry with an odds ratio of 4.22 and a p value of 1.6 x 10(-10), resulting in an odds ratio of 3.65 and a p value of 8.8 x 10(-16) for all studies combined. In vitro studies suggested that the K155Q substitution reduces C3 binding to CFH, potentially creating resistance to inhibition by this factor. This resistance to inhibition in turn was predicted to result in enhanced complement activation.
Zhan et al. (2013) sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes) and then augmented their control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 ARMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: K155Q encoded in the C3 gene, with a case frequency of 1.06%, control frequency of 0.39%, and odds ratio of 2.68; and R1210C (134370.0017) encoded in the CFH gene, with a case frequency of 0.51%, control frequency of 0.02%, and odds ratio of 23.11. The variants suggested decreased inhibition of C3 by CFH, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.
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