HGNC Approved Gene Symbol: C5
SNOMEDCT: 263661007;
Cytogenetic location: 9q33.2 Genomic coordinates (GRCh38): 9:120,952,335-121,074,865 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q33.2 | [Eculizumab, poor response to] | 615749 | Autosomal dominant | 3 |
| C5 deficiency | 609536 | Autosomal recessive | 3 |
Complement component-5 (C5) is a 190-kD glycoprotein composed of 2 disulfide-linked polypeptide chains, alpha (C5a) and beta (C5b), with a molecular mass of 155 and 75 kD, respectively (Tack et al., 1979). Haviland et al. (1991) constructed the complete cDNA sequence of human complement pro-C5, which is predicted to encode a 1,676-amino acid promolecule that contains an 18-amino acid leader peptide and a 4-amino acid linker separating the beta and alpha chains. Northern blot analysis demonstrated a major 6.0-kb C5 transcript, as well as 3.0-kb and 4.8-kb transcripts.
Carney et al. (1991) determined that the C5 gene contains 41 exons that span a genomic region of 79 kb.
By study of somatic cell hybrids using a cDNA probe and by in situ hybridization using the same probe, Jeremiah et al. (1987, 1988) assigned the C5 gene to chromosome 9q22-q34. Wetsel et al. (1988) employed in situ hybridization methods to localize the gene to band 9q32-q34. In their studies, the largest cluster of grains was found at 9q34.1.
Gross (2016) mapped the C5 gene to chromosome 9q33.2 based on an alignment of the C5 sequence (GenBank BC113740) with the genomic sequence (GRCh38).
Karp et al. (2000) found that blockade of C5R1 (C5AR1; 113995) in human monocytes caused marked, dose-dependent inhibition of IL12 production, as well as inhibition of TNFA (191160) secretion and IFNG (147570)-mediated suppression of IL10 (124092) production, although there was no overall effect on IL10 production. These results suggested that deficiency of C5 leads to an antiinflammatory phenotype. Karp et al. (2000) noted that previous genomewide screens had found evidence of linkage of asthma susceptibility to the C5 (Ober et al., 1998; Wjst et al., 1999) and C5R1 (Collaborative Study on the Genetics of Asthma, 1997; Ober et al., 1998) chromosomal regions.
Arbore et al. (2016) found that the NLRP3 (606416) inflammasome assembled in human CD4 (186940)-positive T cells and initiated CASP1 (147678)-dependent IL1B (147720) secretion, thereby promoting IFNG production and T-helper-1 (Th1) differentiation in an autocrine fashion. NLRP3 assembly required intracellular C5 activation and stimulation of C5AR1, and this process was negatively regulated by C5AR2 (609949). Aberrant NLRP3 activity in T cells affected inflammatory responses in patients with cryopyrin-associated periodic syndrome (FCAS1; 120100) and in mouse models of inflammation and infection. Arbore et al. (2016) concluded that NLRP3 inflammasome activity is involved in normal adaptive Th1 responses, as well as in innate immunity.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
C5 Deficiency
In affected members 2 African American families segregating C5 deficiency (C5D; 609536), Wang et al. (1995) identified mutations in the C5 gene (120900.0001-120900.0002).
Poor Response To Eculizumab
In 11 patients of Japanese origin with paroxysmal nocturnal hemoglobinuria (PNH; 300818) who had a poor response to treatment with the C5 inhibitor eculizumab (615749), Nishimura et al. (2014) identified a heterozygous variant in the C5 gene (R885H; 120900.0006). Both the R885H variant and wildtype C5 caused classic complement pathway hemolysis in vitro, but only wildtype C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab. A variant affecting the same residue (R885C; 120900.0007) was found in another PNH patient of Asian descent who had a poor response to eculizumab. The findings indicated that changes at this residue disrupt the eculizumab epitope on C5.
Possible Association With Rheumatoid Arthritis
Plenge et al. (2007) genotyped 317,503 SNPs in a combined case-control study of 1,522 case subjects with rheumatoid arthritis (180300) and 1,850 matched control subjects. All patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). Samples were from 2 datasets: the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality control filters were combined, and SNPs showing a significant association with disease were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis and in control subjects. Plenge et al. (2007) found associations with a SNP on chromosome 9, rs3761847, for all samples tested, with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P = 4 x 10(-14)). This SNP is in linkage disequilibrium with 2 genes relevant to chronic inflammation: TRAF1 (601711) and C5. No coding SNP that might be responsible for this association was found.
Using microarray analysis of pulmonary gene expression and single nucleotide polymorphism (SNP)-based genotyping, Karp et al. (2000) identified C5 on mouse chromosome 2 as a susceptibility locus for allergen-induced airway hyperresponsiveness in a mouse model of asthma (see 600807). Backcross and SNP analysis showed that a 2-bp deletion in the C5 gene of A/J and AKR/J mice led to C5 deficiency, correlating with airway hyperresponsiveness, whereas C5-sufficient strains did not develop asthma. Previous studies had shown that administration of IL12 (161560) to susceptible mice renders them resistant to asthma induction (Gavett et al., 1995).
In C5 deficiency in the mouse, Wetsel et al. (1990) found a deletion of 2 basepairs, TA, near the 5-prime end of the cDNA of the C5 gene. The deletion shifted the reading frame with the creation of a termination codon, UGA, 4 basepairs downstream from the deletion. The same deletion was found in 6 C5-deficient strains but in none of 4 C5-sufficient strains.
Using a C5-specific mAB in ovalbumin (OVA)-sensitized mice, Peng et al. (2005) demonstrated that C5 inhibition attenuated airway response at 3 critical points in the development of asthma: the initiation of inflammation, the maintenance of hyperresponsiveness, and sustainment of an ongoing response to allergen provocation. They found that in the presence of airway inflammation the C5a cleavage product serves as a direct link between the innate immune system and the development of airway hyperresponsiveness by engaging directly with its receptors expressed in airways. Through their potent chemotactic and cell activation properties, both C5a and C5b-9, the membrane attack complex (see 120940), regulate the downstream inflammatory cascade, which results in a massive migration of inflammatory cells into the bronchial airway lumen and triggers the release of multiple harmful inflammatory mediators.
Pickering et al. (2006) investigated the role of C5 activation in a model of membranoproliferative glomerulonephritis that develops spontaneously in complement factor H (CFH; 134370)-deficient mice. Mice deficient in both Cfh and C5 developed membranoproliferative glomerulonephritis, but they showed reduced mortality and glomerular cellularity compared with mice deficient in Cfh alone. In a model of heterologous nephrotoxic nephritis, Cfh-deficient mice showed increased susceptibility to renal inflammation that was critically dependent on C5. Inhibition of C5 by administration of a monoclonal anti-C5 antibody protected Cfh-deficient mice during nephrotoxic nephritis.
In affected members of an African American family with C5 deficiency (C5D; 609536), Wang et al. (1995) identified a C-to-T transition in exon 1 of the C5 gene, resulting in a glutamine-to-stop substitution at codon 84 (Q84X), the first amino acid of the C5 beta chain. This mutation was identified in heterozygosity. The second mutation was not identified.
In affected members of an African American family segregating C5 deficiency (C5D; 609536), Wang et al. (1995) identified a C-to-T transition resulting in an arg1458-to-ter (R1458X) substitution in the alpha chain of C5. This mutation was found in heterozygosity in all affected individuals. The second mutation was not identified in this family.
In 3 affected members of a reportedly nonconsanguineous Spanish family segregating C5 deficiency (C5D; 609536), Delgado-Cervino et al. (2005) identified a homozygous double mutation in which CCC at nucleotide positions 4884-4886 was changed to GC (NM_001735). If the protein resulting from this mutation were stable, it would lack 50 amino acids; however, the protein was very unstable, as no C5 protein was detectable in homozygous patients. Heterozygous family members had 50% C5 activity.
In a 5-year-old Turkish boy with near total C5 deficiency (C5D; 609536), the product of a consanguineous union, Pfarr et al. (2005) identified homozygosity for a 1115A-G transition in exon 10 of the C5 gene that predicts a lys372-to-arg (K372R) substitution. This conservative amino acid substitution would not be predicted to result in complete C5 deficiency; however, the transition changed an exonic splicing enhancer (ESE) from ATCAAG into CATCAG and resulted in complete skipping of exon 10, leading to a frameshift and unstable protein in the affected individual. Both parents and a brother were heterozygous for the mutation and showed 50% C5 activity. Pfarr et al. (2005) concluded that disruption of the ESE by an initially inconsequential sequence alteration resulted in exon skipping and C5 deficiency.
This variant, formerly titled LIVER FIBROSIS, SUSCEPTIBILITY TO, has been reclassified based on the findings of Halangk et al. (2008).
In an association study of C5 haplotypes and genotypes with histologic stages of liver fibrosis in 277 individuals with chronic hepatitis C virus infection (609532), Hillebrandt et al. (2005) found that individuals homozygous for the C5_1 haplotype (rs2300929, rs17611, rs1035019, rs192408) had a significantly higher stage of fibrosis than did individuals carrying at least 1 other allele. Patients with haplotype C5_1 had higher C5 serum levels (174 +/- 6 vs 148 +/- 8 microg/ml(-1); p less than 0.05) consistent with mouse models of liver fibrosis in which C5 deficiency attenuated liver fibrogenesis.
In a study involving 1,435 chronically infected hepatitis C patients and 1,003 patients with chronic liver disease of other etiologies, Halangk et al. (2008) investigated whether the 2 haplotype-tagging SNPs rs17611 and rs2300929 (Hillebrandt et al., 2005) are associated with progressive liver fibrosis. The defined high-risk genotypes and alleles were not associated with advanced fibrosis in hepatitis C patients when chi square testing and logistic regression analysis were applied (rs17611A allele frequency 0.45 in fibrosis stage F0-1 vs 0.43 in F2-4, P = 0.31; rs2300929T 0.91 F0-1 and 0.91 in F2-4, P = 0.82). In the group of patients with liver diseases other than hepatitis C, Halangk et al. (2008) found neither an association of the C5 SNPs with advanced fibrosis nor an overrepresentation of the SNPs in patients with cirrhosis. Halangk et al. (2008) noted that Hillebrandt et al. (2002) had identified C5 as a candidate gene in a quantitative trait locus on mouse chromosome 2 (Hfib2) in experimental crosses of inbred mice with different susceptibilities to liver fibrosis; Halangk et al. (2008) commented that the observed conditions in mice where fibrosis was induced may not reflect the complex disease mechanisms in human liver fibrosis in viral hepatitis, and that the complement system exerts functions in viral defense which might counterpart its effect in fibrogenesis.
In 11 patients of Japanese origin with paroxysmal nocturnal hemoglobinuria (PNH; 300818) who had a poor response to treatment with the C5 inhibitor eculizumab (615749), Nishimura et al. (2014) identified a heterozygous c.2654G-A transition in exon 21 of the C5 gene, resulting in an arg885-to-his (R885H) substitution. These patients were identified among 345 Japanese patients who received eculizumab (rate of poor response, 3.2%). The variant was not found in 7 patients with PNH who had a favorable response to the medication. A heterozygous R885H substitution was found in 10 (3.5%) of 288 healthy Japanese individuals, consistent with the prevalence observed in patients with PNH. The R885H variant was found in 1 of 120 Han Chinese individuals, but not in 100 individuals of British ancestry or 90 individuals of Mexican ancestry. Both the R885H variant and wildtype C5 caused classic pathway hemolysis in vitro, but only wildtype C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab.
In an Argentinian patient of Asian ancestry with paroxysmal nocturnal hemoglobinuria (PNH; 300818) who had a poor response to treatment with the C5 inhibitor eculizumab (615749), Nishimura et al. (2014) identified a heterozygous c.2653C-T transition in exon 21 of the C5 gene, resulting in an arg885-to-cys (R885C) substitution. The R885C variant was not found in 120 Han Chinese individuals, 100 individuals of British ancestry, or 90 individuals of Mexican ancestry. The mutation affected the same residue as R885H (120900.0006), which was shown in vitro to interfere with C5 binding to eculizumab.
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