Alternative titles; symbols
HGNC Approved Gene Symbol: C4B
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38): 6:32,014,795-32,035,418 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.33 | C4B deficiency | 614379 | 3 |
By the process of antigen-antibody crossed electrophoresis, Rosenfeld et al. (1969) demonstrated heterogeneity in the fourth component of complement, C4. Using immunofixation electrophoresis and family studies, O'Neill et al. (1978) demonstrated that 2 different genetic loci control the electrophoretic patterns of C4. Studies by Awdeh and Alper (1980) provided direct evidence that 2 distinct but closely linked genes, C4A and C4B, encode C4.
Both C3 (120700) and C4 are synthesized as single polypeptide chains (Brade et al., 1977; Hall and Colten, 1977). In serum, however, C3 consists of 2 polypeptide chains and C4 consists of 3 (Porter and Reid, 1978).
Roos et al. (1982) showed that the alpha chains of C4A and C4B differ in molecular weight, being 96,000 and 94,000, respectively. Each C4 molecule consists of beta-alpha-gamma subunits, in that sequence, in the pro-C4. The secreted form of C4 is larger in molecular weight than the major plasma form by about 5,000 (Chan et al., 1983). Presumably, the extra piece is removed extracellularly by proteolytic cleavage.
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.
The C4 locus in the guinea pig is linked to the major histocompatibility complex (Shevach et al., 1976) and to Bf (Kronke et al., 1977). The locus in man is in the major histocompatibility region on chromosome 6 (Teisberg et al., 1976; Ochs et al., 1977). The Ss protein of the mouse, determined by a gene that is part of the MHC complex, is homologous to C4 in man (Lachmann et al., 1975; Meo et al., 1975). Thus, linkage homology is maintained in 3 species. Pollack et al. (1980) used the linkage principle (and the tight linkage to HLA) for prenatal diagnosis of C4 deficiency. On the basis of 4 overlapping cosmid clones, Carroll et al. (1984) aligned 4 human complement genes known to map between HLA-D and HLA-B. The C2 and BF genes, which are less than 2 kb apart, are about 30 kb from the 2 C4 genes, which are separated from each other by about 10 kb. Using a chromosome-specific C4 DNA pattern relative to the loss or retention of other MHC genes on the same chromosome, in subclones of a cell line with gamma-ray-induced lesions of the MHC region, Whitehead et al. (1985) could document the location of C4 between HLA-B and HLA-DR.
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.
'Half null' haplotypes, i.e., deletion on one or the other, but not both, C4 loci on any given chromosome, are common in Caucasians (O'Neill et al., 1978).
Awdeh and Alper (1980) introduced a typing system that allowed them to detect 6 common structural variants and a deletion allele at the Rodgers (C4A) locus and 2 structural variants and a deletion allele at the Chido (C4B) locus in whites. See 614374 for information on the Chido/Rodgers blood group system.
Awdeh et al. (1981) analyzed C4 types in relatives of a C4-deficient proband and provided evidence that C4 deficiency (see 614379) resulted 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.
Wank et al. (1984) found a particular rare C4B allele in 25% of 59 unselected patients with primary glomerulonephritis but in only 2% of the normal population--a relative risk of 22.1 for persons with the variant C4B*2.9. The association with the membranoproliferative type was especially strong. Welch and Beischel (1985) suggested that this phenotype was an acquired variant in uremic patients homozygous for C4B1. Studies by Lhotta et al. (1996) confirmed the presence of a uremic variant of B1 in patients with chronic renal failure. The uremic variant disappeared after renal transplantation resulting in normalization of renal function.
Nerl et al. (1984) reported an increase in the frequency of the C4B allele C4B2 in patients with Alzheimer disease (AD; 104300), but Eikelenboom et al. (1988) failed to find a significant association between C4B2 allelic frequency and AD.
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.
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 (120810)- 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.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
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.
In a study of the molecular basis of C4 null alleles, 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 (120810.0001), 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.
Kramer et al. (1991) demonstrated a marked drop in the frequency of the C4-null allele (C4B*Q0) in elderly subjects: in 'young' and 'old' men the frequency was 17.6% and 3.4%, respectively. This suggested that the allele is a negative selection factor for survival. Whether this is a direct effect of the gene or the result of linkage disequilibrium with neighboring genes, such as HLA or CYP21, was discussed.
Fasano et al. (1992) studied a 7-year-old patient with recurrent sinopulmonary infections in whom the rare C4A*Q0,B*Q0 double-null haplotype was shown to be due to a recombination event within the C4B locus in the mother, who possessed a C4A*Q0,B*1 haplotype and a C4A*3,B*1 haplotype. By segregation analysis, they mapped the recombination to a region 3-prime to the unique 6.4-kb TaqI restriction fragment of the maternal C4B locus.
Szalai et al. (2002) found an increase in the frequency of the C4B*Q0 allele in patients with severe coronary artery disease (CAD) who underwent bypass surgery compared to healthy controls (14.2% vs 9.9%). Investigation of specific allelic combinations found that C4B*Q0 in combination with TNF-alpha -308A (191160.0004) was significantly higher in CAD patients, particularly those with preoperative myocardial infarction.
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 systemic lupus erythematosus (SLE; 152700), 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 (GCN) 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 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.
Fontaine et al. (1980) found a common antigenic determinant on human C4b and C3b (120700), supporting a common ancestral origin for C3 and C4. However, C3 is located on chromosome 19.
Ellman et al. (1970) found a deficiency of C4 in guinea pig, where total deficiency was recessive. Hall and Colten (1978) showed that C4 deficiency in guinea pig was due to a defect in translation of specific C4 mRNA on polysomes.
Using C4 -/- and C3 -/- 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.
Awdeh, Z. L., Alper, C. A. Inherited structural polymorphism of the fourth component of human complement. Proc. Nat. Acad. Sci. 77: 3576-3580, 1980. [PubMed: 6932037] [Full Text: https://doi.org/10.1073/pnas.77.6.3576]
Awdeh, Z. L., Ochs, H. D., Alper, C. A. Genetic analysis of C4 deficiency. J. Clin. Invest. 67: 260-263, 1981. [PubMed: 7451653] [Full Text: https://doi.org/10.1172/JCI110021]
Barba, G., Rittner, C., Schneider, P. M. Genetic basis of human complement C4A deficiency: detection of a point mutation leading to nonexpression. J. Clin. Invest. 91: 1681-1686, 1993. [PubMed: 8473511] [Full Text: https://doi.org/10.1172/JCI116377]
Boteva, L., Morris, D. L., Cortes-Hernandez, J., Martin, J., Vyse, T. J., Fernando, M. M. A. Genetically determined partial complement C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Am. J. Hum. Genet. 90: 445-456, 2012. [PubMed: 22387014] [Full Text: https://doi.org/10.1016/j.ajhg.2012.01.012]
Brade, V., Hall, R. E., Colten, H. R. Biosynthesis of pro-C3, a precursor of the third component of complement. J. Exp. Med. 146: 759-765, 1977. [PubMed: 561154] [Full Text: https://doi.org/10.1084/jem.146.3.759]
Braun, L., Schneider, P. M., Giles, C. M., Bertrams, J., Rittner, C. Null alleles of human complement C4: evidence for pseudogenes at the C4A locus and for gene conversion at the C4B locus. J. Exp. Med. 171: 129-140, 1990. [PubMed: 2295875] [Full Text: https://doi.org/10.1084/jem.171.1.129]
Carroll, M. C., Alper, C. A. Polymorphism and molecular genetics of human C4. Brit. Med. Bull. 43: 50-65, 1987. [PubMed: 3315101] [Full Text: https://doi.org/10.1093/oxfordjournals.bmb.a072176]
Carroll, M. C., Campbell, R. D., Bentley, D. R., Porter, R. R. A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B. Nature 307: 237-241, 1984. [PubMed: 6559257] [Full Text: https://doi.org/10.1038/307237a0]
Carroll, M. C., Fathallah, D. M., Bergamaschini, L., Alicot, E. M., Isenman, D. E. Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A. Proc. Nat. Acad. Sci. 87: 6868-6872, 1990. [PubMed: 2395880] [Full Text: https://doi.org/10.1073/pnas.87.17.6868]
Carroll, M. C., Porter, R. R. Cloning of a human complement component C4 gene. Proc. Nat. Acad. Sci. 80: 264-267, 1983. [PubMed: 6572000] [Full Text: https://doi.org/10.1073/pnas.80.1.264]
Chan, A. C., Mitchell, K. R., Munns, T. W., Karp, D. R., Atkinson, J. P. Identification and partial characterization of the secreted form of the fourth component of human complement: evidence that it is different from major plasma form. Proc. Nat. Acad. Sci. 80: 268-272, 1983. [PubMed: 6572001] [Full Text: https://doi.org/10.1073/pnas.80.1.268]
Chung, E. K., Yang, Y., Rennebohm, R. M., Lokki, M.-L., Higgins, G. C., Jones, K. N., Zhou, B., Blanchong, C. A., Yu, C. Y. Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex. Am. J. Hum. Genet. 71: 823-837, 2002. [PubMed: 12226794] [Full Text: https://doi.org/10.1086/342777]
Chung, E. K., Yang, Y., Rupert, K. L., Jones, K. N., Rennebohm, R. M., Blanchong, C. A., Yu, C. Y. Determining the one, two, three, or four long and short loci of human complement C4 in a major histocompatibility complex haplotype encoding C4A or C4B proteins. Am. J. Hum. Genet. 71: 810-822, 2002. [PubMed: 12224044] [Full Text: https://doi.org/10.1086/342778]
Cream, J. J., Olaisen, B., Teisberg, P., Soler, A. V., Thompson, R. A. Genetic basis of acquired C4 deficiency. Clin. Genet. 16: 297-300, 1979. [PubMed: 519900] [Full Text: https://doi.org/10.1111/j.1399-0004.1979.tb01005.x]
Cunningham-Rundles, C., Dupont, B., Jersild, C., Tegoli, C., Whitsett, C., Good, R. A. Are HLA and Chido related antigenic groups? Transplant. Proc. 9: 33-38, 1977. [PubMed: 300929]
Cunningham-Rundles, C., Tegoli, J., Dupont, B., Whitsett, C., Good, R. A. Chemical studies on the Chido antigen. Transplant. Proc. 9: 647-652, 1977. [PubMed: 325797]
Curman, B., Ostberg, L., Sandberg, L., Malmheden-Erikkson, I., Stalenheim, G., Rask, L., Peterson, P. A. H-2 linked Ss protein is C-4 component of complement. Nature 258: 243-245, 1975. [PubMed: 1202351] [Full Text: https://doi.org/10.1038/258243a0]
Eikelenboom, P., Goetz, J., Pronk, J. C., Hauptmann, G. Complement C4 phenotypes in dementia of the Alzheimer type. Hum. Hered. 38: 48-51, 1988. [PubMed: 3350531] [Full Text: https://doi.org/10.1159/000153754]
Ellman, L., Green, I., Frank, M. Genetically controlled total deficiency of the fourth component of complement in the guinea pig. Science 170: 74-75, 1970. [PubMed: 4989151] [Full Text: https://doi.org/10.1126/science.170.3953.74]
Fasano, M. B., Winkelstein, J. A., LaRosa, T., Bias, W. B., McLean, R. H. A unique recombination event resulting in a C4A*Q0,C4B*Q0 double null haplotype. J. Clin. Invest. 90: 1180-1184, 1992. [PubMed: 1401055] [Full Text: https://doi.org/10.1172/JCI115978]
Fontaine, M., Daveau, M., Lebreton, J. P. A common antigenic determinant on human C4b and C3b. Molec. Immun. 17: 1075-1078, 1980. [PubMed: 6160392] [Full Text: https://doi.org/10.1016/0161-5890(80)90102-9]
Giles, C. M. A new genetic variant for Chido. Vox Sang. 46: 149-156, 1984. [PubMed: 6710967] [Full Text: https://doi.org/10.1111/j.1423-0410.1984.tb00067.x]
Hall, R. E., Colten, H. R. Cell-free synthesis of the fourth component of guinea pig complement (C4): identification of a precursor of serum C4 (pro-C4). Proc. Nat. Acad. Sci. 74: 1707-1710, 1977. [PubMed: 266210] [Full Text: https://doi.org/10.1073/pnas.74.4.1707]
Hall, R. E., Colten, H. R. Genetic defect in biosynthesis of the precursor form of the fourth component of complement. Science 199: 69-70, 1978. [PubMed: 17569484] [Full Text: https://doi.org/10.1126/science.199.4324.69]
Hobart, M. J., Lachmann, P. J. Allotypes of complement components in man. Transplant. Rev. 32: 26-42, 1976. [PubMed: 824769] [Full Text: https://doi.org/10.1111/j.1600-065x.1976.tb00227.x]
Kamitaki, N., Sekar, A., Handsaker, R. E., de Rivera, H., Tooley, K., Morris, D. L., Taylor, K. E., Whelan, C. W., Tombleson, P., Loohuis, L. M. O., Schizophrenia Working Group of the Psychiatric Genomics Consortium, Boehnke, M., and 12 others. Complement genes contribute sex-based vulnerability in diverse disorders. Nature 582: 577-581, 2020. [PubMed: 32499649] [Full Text: https://doi.org/10.1038/s41586-020-2277-x]
Kramer, J., Fulop, T., Rajczy, K., Ahn Tuan, N., Fust, G. A marked drop in the incidence of the null allele of the B gene of the fourth component of complement (C4B*Q0) in elderly subjects: C4B*Q0 as a probable negative selection factor for survival. Hum. Genet. 86: 595-598, 1991. [PubMed: 2026423] [Full Text: https://doi.org/10.1007/BF00201547]
Kronke, M., Hadding, U., Geczy, A. F., de Weck, A. L., Bitter-Suermann, D. Linkage of guinea pig Bf and C4 to the GPLA. J. Immun. 119: 2016-2018, 1977. [PubMed: 915289]
Lachmann, P. J., Grennan, D., Martin, A., Demant, P. Identification of Ss protein as murine C4. Nature 258: 242-243, 1975. [PubMed: 1202350] [Full Text: https://doi.org/10.1038/258242a0]
Lhotta, K., Schlogl, A., Uring-Lambert, B., Kronenberg, F., Konig, P. Complement C4 phenotypes in patients with end-stage renal disease. Nephron 72: 442-446, 1996. [PubMed: 8852494] [Full Text: https://doi.org/10.1159/000188910]
Mascart-Lemone, F., Hauptmann, G., Goetz, J., Duchateau, J., Delespesse, G., Vray, B., Dab, I. Genetic deficiency of C4 presenting with recurrent infections and a SLE-like disease: genetic and immunologic studies. Am. J. Med. 75: 295-304, 1983. [PubMed: 6881182] [Full Text: https://doi.org/10.1016/0002-9343(83)91208-1]
Meo, T., Krasteff, T., Shreffler, D. C. Immunochemical characterization of murine H-2 controlled Ss (serum substance) protein through identification of its human homologue as the fourth component of complement. Proc. Nat. Acad. Sci. 72: 4536-4540, 1975. [PubMed: 53836] [Full Text: https://doi.org/10.1073/pnas.72.11.4536]
Nerl, C., Mayeux, R., O'Neill, G. J. HLA-linked complement markers in Alzheimer's and Parkinson's disease C4 variant (C4B2)--a possible marker for senile dementia of the Alzheimer type. Neurology 34: 310-314, 1984. [PubMed: 6538270] [Full Text: https://doi.org/10.1212/wnl.34.3.310]
O'Neill, G. J., Yang, S. Y., Dupont, B. Chido and Rodgers blood groups: relationships to C4 and HLA. Transplant. Proc. 10: 749-751, 1978. [PubMed: 734745]
O'Neill, G. J., Yang, S. Y., Dupont, B. Two HLA-linked loci controlling the fourth component of human complement. Proc. Nat. Acad. Sci. 75: 5165-5169, 1978. [PubMed: 368809] [Full Text: https://doi.org/10.1073/pnas.75.10.5165]
O'Neill, G. J., Yang, S. Y., Tegoli, J., Berger, R., Dupont, B. Chido and Rodgers blood groups are distinct antigenic components of human C4. Nature 273: 668-670, 1978. [PubMed: 78453] [Full Text: https://doi.org/10.1038/273668a0]
O'Neill, G. J. The genetic control of Chido and Rodgers blood group substances. Semin. Hemat. 18: 32-38, 1981. [PubMed: 7010610]
Ochs, H. D., Rosenfeld, S. I., Thomas, E. D., Giblett, E. R., Alper, C. A., Dupont, B., Schaller, J. G., Gilliland, B. C., Hansen, J. A., Wedgwood, R. J. Linkage between the gene (or genes) controlling synthesis of the fourth component of complement and the major histocompatibility complex. New Eng. J. Med. 296: 470-475, 1977. [PubMed: 138091] [Full Text: https://doi.org/10.1056/NEJM197703032960902]
Olaisen, B., Teisberg, P., Nordhagen, R., Michaelsen, T., Gedde-Dahl, T., Jr. Human complement C4 locus is duplicated on some chromosomes. Nature 279: 736-737, 1979. [PubMed: 450123] [Full Text: https://doi.org/10.1038/279736a0]
Palsdottir, A., Fossdal, R., Arnason, A., Edwards, J. H., Jensson, O. Heterogeneity of human C4 gene size: a large intron (6.5 kb) is present in all C4A genes and some C4B genes. Immunogenetics 25: 299-304, 1987. [PubMed: 2883116] [Full Text: https://doi.org/10.1007/BF00404422]
Partanen, J., Kere, J., Wessberg, S., Koskimies, S. Determination of deletion sizes in the MHC-linked complement C4 and steroid 21-hydroxylase genes by pulsed-field gel electrophoresis. Genomics 5: 345-349, 1989. [PubMed: 2551816] [Full Text: https://doi.org/10.1016/0888-7543(89)90067-0]
Partanen, J., Koskimies, S., Johansson, E. C4 null phenotypes among lupus erythematosus patients are predominantly the result of deletions covering C4 and closely linked 21-hydroxylase A genes. J. Med. Genet. 25: 387-391, 1988. [PubMed: 3260957] [Full Text: https://doi.org/10.1136/jmg.25.6.387]
Petersen, G. B., Sorensen, I. J., Buskjaer, L., Lamm, L. U. Genetic studies of complement C4 in man. Hum. Genet. 53: 31-36, 1979. [PubMed: 535900] [Full Text: https://doi.org/10.1007/BF00289447]
Pollack, M. S., Ochs, H. D., Dupont, B. HLA typing of cultured amniotic cells for the prenatal diagnosis of complement C4 deficiency. Clin. Genet. 18: 197-200, 1980. [PubMed: 7438500] [Full Text: https://doi.org/10.1111/j.1399-0004.1980.tb00871.x]
Porter, R. R., Reid, K. B. M. The biochemistry of complement. Nature 275: 699-704, 1978. [PubMed: 703835] [Full Text: https://doi.org/10.1038/275699a0]
Prentice, H. L., Schneider, P. M., Strominger, J. L. C4B gene polymorphism detected in a human cosmid clone. Immunogenetics 23: 274-276, 1986. [PubMed: 3009318] [Full Text: https://doi.org/10.1007/BF00373024]
Rittner, C., Bertrams, J. On the significance of C2, C4, and factor B polymorphisms in disease. Hum. Genet. 56: 235-247, 1981. [PubMed: 7016719] [Full Text: https://doi.org/10.1007/BF00274674]
Rittner, C., Hauptmann, G., Grosse-Wilde, H., Grosshans, E., Tongio, M. M., Mayer, S. Linkage between HL-A (major histocompatibility complex) and genes controlling the fourth component of complement. In: Kissmeyer-Nielsen, F. (ed.): Histocompatibility Testing 1975. Copenhagen: Munksgaard 1976. Pp. 945-953.
Roos, M. H., Mollenhauer, E., Demant, P., Rittner, C. A molecular basis for the two locus model of human complement component C4. Nature 298: 854-856, 1982. [PubMed: 6180321] [Full Text: https://doi.org/10.1038/298854a0]
Rosenfeld, S. I., Ruddy, S., Austen, K. F. Structural polymorphism of the fourth component of human complement. J. Clin. Invest. 48: 2283-2292, 1969. [PubMed: 5389795] [Full Text: https://doi.org/10.1172/JCI106194]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Schaller, J. G., Gilliland, B. G., Ochs, H. D., Leddy, J. P., Agodoa, L. C. Y., Rosenfeld, S. I. Severe systemic lupus erythematosus with nephritis in a boy with deficiency of the fourth component of complement. Arthritis Rheum. 20: 1519-1525, 1977. [PubMed: 921824] [Full Text: https://doi.org/10.1002/art.1780200812]
Schneider, P. M., Carroll, M. C., Alper, C. A., Rittner, C., Whitehead, A. S., Yunis, E. J., Colten, H. R. Polymorphism of the human complement C4 and steroid 21-hydroxylase genes: restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants. J. Clin. Invest. 78: 650-657, 1986. [PubMed: 3018042] [Full Text: https://doi.org/10.1172/JCI112623]
Schneider, P. M., Witzel-Schlomp, K., Rittner, C., Zhang, L. The endogenous retroviral insertion in the human complement C4 gene modulates the expression of homologous genes by antisense inhibition. Immunogenetics 53: 1-9, 2001. [PubMed: 11261924] [Full Text: https://doi.org/10.1007/s002510000288]
Shevach, E. M., Frank, M. M., Green, I. Linkage of gene controlling the synthesis of the fourth component of complement to the major histocompatibility complex of the guinea pig. Immunogenetics 3: 595-602, 1976.
Shreffler, D. C. The S region of the mouse major histocompatibility complex (H-2): genetic variation and functional role in complement system. Transplant. Rev. 32: 140-167, 1976. [PubMed: 824768] [Full Text: https://doi.org/10.1111/j.1600-065x.1976.tb00232.x]
Suto, Y., Tokunaga, K., Watanabe, Y., Hirai, M. Visual demonstration of the organization of the human complement C4 and 21-hydroxylase genes by high-resolution fluorescence in situ hybridization. Genomics 33: 321-324, 1996. [PubMed: 8660986] [Full Text: https://doi.org/10.1006/geno.1996.0202]
Szalai, C., Fust, G., Duba, J., Kramer, J., Romics, L., Prohaszka, Z., Csaszar, A. Association of polymorphisms and allelic combinations in the tumour necrosis factor-alpha-complement MHC region with coronary artery disease. J. Med. Genet. 39: 46-51, 2002. [PubMed: 11826025] [Full Text: https://doi.org/10.1136/jmg.39.1.46]
Teisberg, P., Akesson, I., Olaisen, B., Gedde-Dahl, T., Jr., Thorsby, E. Genetic polymorphism of C4 in man and localization of a structural C4 locus to the HLA gene complex of chromosome 6. Nature 264: 253-254, 1976. [PubMed: 1088823] [Full Text: https://doi.org/10.1038/264253a0]
Wank, R., Schendel, D. J., O'Neill, G. J., Riethmuller, G., Held, E., Feucht, H. E. Rare variant of complement C4 is seen in high frequency in patients with primary glomerulonephritis. Lancet 323: 872-874, 1984. Note: Originally Volume I. [PubMed: 6143186] [Full Text: https://doi.org/10.1016/s0140-6736(84)91339-4]
Welch, T. R., Beischel, L. S., Choi, E., Balakrishnan, K., Bishof, N. A. Uniparental isodisomy 6 associated with deficiency of the fourth component of complement. J. Clin. Invest. 86: 675-678, 1990. [PubMed: 2384609] [Full Text: https://doi.org/10.1172/JCI114760]
Welch, T. R., Beischel, L. C4 uremic variant: an acquired C4 allotype. Immunogenetics 22: 553-562, 1985. [PubMed: 3865892] [Full Text: https://doi.org/10.1007/BF00430303]
Whitehead, A. S., Colten, H. R., Chang, C. C., Demars, R. Localization of the human MHC-linked complement genes between HLA-B and HLA-DR by using HLA mutant cell lines. J. Immun. 134: 641-643, 1985. [PubMed: 3917284]
Yammani, R. D., Leyva, M. A., Jennings, R. N., Haas, K. M. C4 deficiency is a predisposing factor for Streptococcus pneumoniae-induced autoantibody production. J. Immun. 193: 5434-5443, 2014. [PubMed: 25339671] [Full Text: https://doi.org/10.4049/jimmunol.1401462]
Yang, Y., Chung, E. K., Wu, Y. L., Savelli, S. L., Nagaraja, H. N., Zhou, B., Hebert, M., Jones, K. N., Shu, Y., Kitzmiller, K., Blanchong, C. A., McBride, K. L., and 11 others. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am. J. Hum. Genet. 80: 1037-1054, 2007. [PubMed: 17503323] [Full Text: https://doi.org/10.1086/518257]
Yu, C. Y., Belt, K. T., Giles, C. M., Campbell, R. D., Porter, R. R. Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity. EMBO J. 5: 2873-2881, 1986. [PubMed: 2431902] [Full Text: https://doi.org/10.1002/j.1460-2075.1986.tb04582.x]
Yu, C. Y. The complete exon-intron structure of a human complement component C4A gene: DNA sequences, polymorphism, and linkage to the 21-hydroxylase gene. J. Immun. 146: 1057-1066, 1991. [PubMed: 1988494]