Alternative titles; symbols
HGNC Approved Gene Symbol: C4A
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:31,982,057-32,002,681 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | [Blood group, Rodgers] | 614374 | 3 | |
| C4a deficiency | 614380 | Autosomal recessive | 3 |
O'Neill et al. (1978) described an electrophoretic polymorphism of C4. Using immunofixation electrophoresis, they found 3 clusters of bands in EDTA plasma: 4 fast-moving anodal bands (F), 4 slow-moving cathodal bands (S), and a combination of F and S bands (FS). Family data, including HLA haplotyping, were compatible with the existence of 2 loci, 1 controlling the presence or absence of the 4 anodal (F) bands and a second serving the same role for the S bands. C4F and C4S were closely linked to HLA-B. These findings were consistent with those suggesting that the Chido and the Rodgers blood groups (see 614374) are antigenic characteristics of C4, but are not allelic. Polymorphism was thought to exist, i.e., some persons have 2 C4 loci and others 1.
Studies by Awdeh and Alper (1980) provided direct evidence that 2 distinct but closely linked genes encode C4. They referred to these genes using new designations, C4A and C4B (120820), in place of C4S and C4F, respectively.
Yu et al. (1986) demonstrated that C4A and C4B differ by only 4 amino acids at position 1101 to 1106. Over this region C4A has the sequence PCPVLD, while C4B has the sequence LSPVIH.
In a review of the molecular genetics of C4, Carroll and Alper (1987) stated that C4A and C4B differ by 14 nucleotides. Allotypic and serologic differences appear to result from single amino acid substitutions.
Palsdottir et al. (1987) showed that the 2 human C4 genes differ in length because of the presence or absence of a 6.5-kb intron near the 5-prime end of the gene. The large intron was present in all C4A genes but only in some C4B genes.
The C4A gene is usually approximately 22 kb long, whereas the C4B gene is polymorphic in size, either 22 or 16 kb. This size variation is due to the presence of a 7-kb intron located approximately 2.5 kb from the 5-prime end of the C4 genes (Prentice et al., 1986; Yu, 1991).
A 6.4-kb insertion present in intron 9 in 60% of human C4 genes contains the complete human endogenous retrovirus-K(C4), or HERV-K(C4), in the reverse orientation to the C4 coding sequence. By expressing open reading frames from the HERV sequence in mouse cells transfected with either C4A or C4B, Schneider et al. (2001) demonstrated that the HERV-K(C4) antisense transcripts are present, that expression of the HERV-like constructs is significantly downregulated in cells expressing C4, and that gamma-interferon (147520)-induced upregulation of C4 enhances the downregulation of HERV in a dose-dependent manner.
Bruun-Petersen et al. (1981) found 1 recombinant between C4 and HLA-B in 154 meioses, giving a map distance of 0.6 cM. Another recombinant between C4 and HLA-D was found in 101 meioses, giving a map distance of 1.0 cM. They found marked linkage disequilibrium with both HLA-B and HLA-D/DR, especially with the former. The findings are consistent with the previous estimate of 1.8 cM for the HLA-B--HLA-D map distance (Lamm et al., 1977). The authors stated a preference of C4F and C4S, because of the possibility of confusion of C4A and C4B with HLA-A and HLA-B.
Olaisen et al. (1983) studied gene order and relative distance in the HLA-A to HLA-B segment of MHC by a method based on allelic association (linkage disequilibrium). A total of 701 haplotypes based on typing of HLA-A, HLA-B, HLA-C, HLA-D/DR, C4, C2 and BF were studied. The study confirmed localization of the complement loci between HLA-D and HLA-B; suggested the order HLA-D--BF--C4--C2--HLA-B (perhaps with C4A on the HLA-B side of C4B) and suggested the following relative distances (given a length of 0.8 cM for the HLA-A to HLA-B segment): D--0.44--BF--0.04--C4--0.11--C2--0.12--B.
The C4A and C4B genes are tandemly arranged with the CYP21A and CYP21B genes (see 613815), each located 3-prime to the C4A and C4B genes, respectively (Carroll et al., 1985; White et al., 1985).
Wilton and Charlton (1986) used the haplotype method to determine the sequence of class III genes in relation to MHC genes: C4 is closest to HLA-B and BF is closest to HLA-DR. HLA-B is telomeric to 21B. C4B, 21A, C4A, BF, and C2 then follow 21B in that order covering 120 kb.
Robinson et al. (1985) gave mapping information on the C4 genes derived from family studies using RFLPs.
Suto et al. (1996) demonstrated that the MHC class III region can be examined directly and visually by multicolor fluorescence in situ hybridization using stretched DNA preparations. By varying the time of treatment with SDS solution, the extent of the DNA stretching could be varied. The authors thus determined the organization of the human C4A, C4B, 210HA (CYP21A), and 210HB (CYP21B) genes. The authors stated that the method should be useful for rapid screening of gene deletions and duplications and analysis of gene organization.
The C4B isotype of C4 displays 3- to 4-fold greater hemolytic activity than does the C4A isotype. Carroll et al. (1990) demonstrated that a conversion of residue 1106 from histidine to aspartic acid in C4B changed the functional activity to that of C4A.
Awdeh and Alper (1980) counted at least 6 structural variants and a deletion allele at the C4A locus and 2 structural variants and a deletion allele at the C4B locus. No crossovers were found between the 2 C4 loci.
Awdeh et al. (1981) analyzed C4 types in relatives of a C4-deficient proband (see 614380) and provided evidence that the deficiency results from homozygosity for a rare, double-null haplotype. The family contained persons with 1, 2, 3, or 4 expressed C4 genes, and the mean serum C4 levels roughly reflected the number of structural genes present.
Palsdottir et al. (1983) identified a different genomic variant of C4 using the restriction enzyme BglII.
Whitehead et al. (1984) used a cDNA probe for C4 to demonstrate DNA polymorphism of the C4 genes. Furthermore, they validated its potential for the study of 21-hydroxylase deficiency (201910) through linkage.
In a review of the molecular genetics of C4, Carroll and Alper (1987) reported that about half of C4-null genes are the result of DNA deletions, some of which also involve nearby steroid 21-hydroxylase genes.
By molecular studies at the DNA level, Schneider et al. (1986) found that about half of the C4 genes typed as C4 null were deleted. Several unrecognized homoduplication genes were detected. Null alleles at either the C4A locus or the C4B locus, designated C4AQ0 and C4BQ0, respectively, appeared to be relatively common, occurring at the C4A locus in about 10% of normal persons and at the C4B locus in about 16% of normal persons. The double-null haplotype was very rare.
Teisberg et al. (1988) studied RFLP patterns in the C4 gene region, determining C4 haplotype pattern and C4 gene number. Among 76 haplotypes, 12 had 1 C4 gene, 58 had 2 C4 genes, and 6 had 3 C4 genes. The finding fitted satisfactorily with the hypothesis that the 1-gene and 3-gene haplotypes originated through unequal crossing-over between chromosomes carrying duplicated C4 genes.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
To evaluate the molecular basis of the C4-null phenotypes, Partanen et al. (1988) used Southern blotting techniques to analyze genomic DNA from 23 patients with systemic lupus erythematosus (SLE; 152700) and from healthy controls. They confirmed the earlier findings of high frequencies of C4-null phenotypes and of HLA-B8,DR3 antigens. In addition, they found that among the patients most of both the C4A- and C4B-null phenotypes resulted from gene deletions. Among the controls, only the C4A-null phenotypes were predominantly the result of gene deletions. In all SLE cases, the C4 gene deletions extended also to a closely linked pseudogene, CYP21A (613815). Altogether, 52% of the patients and 26% of the controls carried a C4/CYP21A deletion. Partanen et al. (1989) found that deletions in 6p involving the C4 and CYP21 loci fell within the range of 30 to 38 kb, as determined by pulsed-field gel electrophoresis. Because the deletion sizes in most other gene clusters were more heterogeneous, the results suggested to Partanen et al. (1989) the involvement of a specific mechanism in the generation of C4/CYP21 deletions.
In a 9-year-old girl with SLE and complete C4 deficiency, Welch et al. (1990) found uniparental isodisomy 6. The girl had 2 identical chromosome 6 haplotypes from the father and none from the mother.
The C4 molecule has 3 polypeptide chains, alpha, beta and gamma, all encoded by a single gene. This is true for the gene product(s) of both C4A and C4B. Ebanks et al. (1992) demonstrated an amino acid substitution at residue 458 of the beta chain, which accounts for the defect in classical pathway C5 convertase activity of allotype C4A6. Their findings suggested that arg458 of the beta chain of C4 contributes to the C5-binding site of the molecule.
Chung et al. (2002) stated that complement component C4 illustrates one of the most unusual phenomena in genetic diversity. The frequent germline variation in the number and size of C4 genes among different individuals is extraordinary. The copy number of C4 genes in a diploid human genome (i.e., the gene dosage) predominantly varies from 2 to 6 in the white population. Each of these genes encodes a C4A or C4B protein. C4 is a constituent of the 4-gene module termed the 'RCCX,' which takes its designation from RP1 (see STK19; 604977), C4, CYP21, and TNXB (600985). The 4-gene module duplicates as a discrete genetic unit in the class III region of the major histocompatibility complex. Chung et al. (2002) developed a comprehensive series of novel or improved techniques to determine the total gene number of C4 and the relative dosages of C4A and C4B in the diploid genome. Chung et al. (2002) applied these techniques to elucidate the complement C4 polymorphisms in gene sizes, gene numbers, and protein isotypes as well as their gene orders. In 4 informative families, a complex pattern of genetic diversity for RCCX haplotypes in 1, 2, 3, and 4 C4 genes was demonstrated; each C4 gene may be long or short, encoding a C4A or C4B protein. Chung et al. (2002) suggested that this diversity may be related to different intrinsic strengths among humans to defend against infections and susceptibilities to autoimmune diseases.
Pursuing the role of copy number variation (CNV) of C4 genes in susceptibility to autoimmune disease, Yang et al. (2007) investigated C4 gene CNV in 1,241 European Americans, including patients with SLE, their first-degree relatives, and unrelated healthy subjects. The gene copy number (GCN) varied from 2 to 6 for total C4, from 0 to 5 for C4A, and from 0 to 4 for C4B. Four copies of total C4, 2 copies of C4A, and 2 copies of C4B were the most common GCN counts, but each constituted only between one half and three quarters of the study population. Long C4 genes were strongly correlated with C4A (P less than 0.0001). Short C4 genes were correlated with C4B (P less than 0.0001). In comparison with healthy subjects, patients with SLE clearly had the GCN of total C4 and C4A shifting to the lower side. The risk of SLE disease susceptibility significantly increased among subjects with only 2 copies of total C4 but decreased in those with 5 copies or more of C4. Both 0 copies and 1 copies were risk factors for SLE, whereas 3 or more copies of C4A appeared to be protective. Family-based association tests suggested that a specific haplotype with a single short C4B in tight linkage disequilibrium with the -308A allele of tumor necrosis factor-alpha (TNFA; 191160.0004) was more likely to be transmitted to patients with SLE. The work demonstrated how gene CNV and its related polymorphisms are associated with the susceptibility to a human complex disease.
Boteva et al. (2012) genotyped 1,028 SLE cases, including 501 patients from the UK and 537 from Spain, and 1,179 controls for gene copy number of total C4, C4A, C4B, and the 2-bp insertion SNP (C4AQ0; 120810.0001) resulting in a null allele. The loss-of-function SNP in C4A was not associated with SLE in either population. Boteva et al. (2012) used multiple logistic regression to determine the independence of C4 CNV from known SNP and HLA-DRB1 associations. Overall, the findings indicated that partial C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Although complete homozygous deficiency of complement C4 is one of the strongest genetic risk factors for SLE, partial C4 deficiency states do not independently predispose to the disease.
Kamitaki et al. (2020) noted that SLE and Sjogren syndrome (see 270150) affect 9 times more women than men, whereas schizophrenia (181500) affects men with greater frequency and severity than women. Kamitaki et al. (2020) showed that variation in the C4A and C4B genes generated 7-fold variation in risk for SLE and 16-fold variation in risk for Sjogren syndrome among individuals with common C4 genotypes, with C4A offering stronger protection than C4B in both illnesses. C4 alleles that increased risk for schizophrenia greatly reduced risk for SLE and Sjogren syndrome. In all 3 illnesses, C4 alleles acted more strongly in men than in women, with common combinations of C4A and C4B generating 14-fold variation in risk for SLE, 31-fold variation in risk for Sjogren syndrome, and 1.7-fold variation in schizophrenia risk among men versus 6-fold, 15-fold, and 1.26-fold variation in risk among women, respectively. Protein levels of both C4 and its effector C3 (120700) were higher in cerebrospinal fluid and plasma in men compared with women among adults between 20 and 50 years of age, corresponding to the ages of differential disease vulnerability. Kamitaki et al. (2020) concluded that sex differences in complement protein levels may explain the more potent effects of C4 alleles in men, the greater risk in women of SLE and Sjogren syndrome, and the greater vulnerability in men to schizophrenia.
The WHO-IUIS Nomenclature Sub-Committee (1993) made recommendations for C4 nomenclature.
In C4 deficiency of the guinea pig, Whitehead et al. (1983) observed a C4 precursor RNA but no mature mRNA, suggesting that the defect lies in RNA processing.
In the mouse, Ss and Slp are separate antigenic specificities corresponding to human C4; they map within the major histocompatibility complex in the mouse also. The symbol Slp for the mouse locus comes from 'sex-limited protein.' Slp expression in many strains is limited to males and is androgen dependent. However, female expression is also observed in rare strains, due to 1 or more unlinked genes termed 'regulator of sex limitation' (rsl). Jiang et al. (1996) demonstrated that female expression of Slp results from homozygous recessive alleles at a single autosomal locus that maps to a 2.2-cM interval on mouse chromosome 13. The locus Rsl was found not only to enable expression in females but also to increase expression in males. The findings suggested that the expression of Slp and perhaps other sexually dimorphic proteins is regulated by 2 pathways, 1 that is dependent upon RSL but not androgens and another that is Rsl-independent but requires androgens.
Bullous pemphigoid (BP) is a subepidermal blistering skin disorder of the elderly associated with autoantibodies directed against the hemidesmosomal proteins BP180 (COL17A1; 113811) and BP230 (DST; 113810). Nelson et al. (2006) found that mice deficient in the alternative pathway complement factor B (CFB; 138470) had delayed and less intense subepidermal blisters following challenge with anti-BP180. Mice lacking the classical complement component C4 were resistant to experimental BP and had significantly reduced mast cell degranulation and neutrophil skin infiltration. BP disease in C4-deficient mice could be restored by treatment with a mast cell degranulating agent or by injection of the neutrophil chemoattractant IL8 (146930). Nelson et al. (2006) concluded that complement activation via the alternative and classical pathways is necessary for blister formation in experimental BP.
Using C4 -/- and C3 (120700) -/- mice, Yammani et al. (2014) found that only C4 -/- mice produced persistent IgA double-stranded DNA (dsDNA) autoantibodies in response to pneumococcal infection or vaccination with pneumococcal polysaccharide (PPS). This effect was partially due to cross-reactivity between pneumococcal antigens and dsDNA, as well as PPS-associated TLR2 (603028) agonists. The response was more pronounced in female C4 -/- mice. Increased IgA was associated with increased deposition in kidneys. Administration of a Tlr2 agonist also induced autoantibody production, whereas a Tlr2 antagonist at the time of PPS vaccination blocked autoantibody, but not PPS-specific antibody, production. Yammani et al. (2014) concluded that C4 plays an important role in suppressing autoantibody production elicited by cross-reactive antigens and TLR2 agonists associated with Streptococcus pneumoniae.
In a study of the molecular basis of C4 null alleles (see 614380), Braun et al. (1990) found evidence for defective genes at the C4A locus and for gene conversion at the C4B locus as demonstrated by the presence of C4A-specific sequences. To characterize further the molecular basis of these nonexpressed C4A genes, Barba et al. (1993) selected 9 pairs of PCR primers from flanking genomic intron sequences to amplify all 41 exons from individuals with a defective C4A gene. The amplified products were subjected to single-strand conformation polymorphism (SSCP) analysis to detect possible mutations. PCR products exhibiting a variation in the SSCP pattern were sequenced directly. In 10 of 12 individuals, a 2-bp insertion in exon 29, leading to nonexpression due to creation of a termination codon, was detected. The insertion was linked to the haplotype HLA-B60-DR6 in 7 cases. In 1 of the other 2 individuals without this mutation, evidence was obtained for gene conversion to the C4B isotype. They suggested that the insertion was due to slipped mispairing mediated by a direct repeat or run of identical bases since the original sequence of the insertion site CTC was changed to CTCTC by addition of a CT or a TC dinucleotide. Since the reading frame was shifted, a complete change in the amino acid sequence resulted, followed by a termination codon at the beginning of exon 30.
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