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PubMed1999

Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes.

The complement protein C4, encoded by two genes (C4A and C4B) on chromosome 6p, is the most polymorphic among the MHC III gene products. We investigated the molecular basis of C4 deficiency in a Finnish woman with systemic lupus erythematosus. C4-specific mRNA was present at low concentrations in C4-deficient (C4D) patient fibroblasts, but no pro-C4 protein was detected. This defect in C4 expression was specific in that synthesis of two other complement proteins was normal. Analysis of genomic DNA showed that the proposita had both deleted and nonexpressed C4 genes. Each of her nonexpressed genes, a C4A null gene inherited from the mother, a C4A null gene, and a C4B null gene inherited from the father, all contained an identical 2-bp insertion (TC) after nucleotide 5880 in exon 29, providing the first confirmatory proof of the C4B pseudogene. This mutation has been previously found only in C4A null genes. Although the exon 29/30 junction is spliced accurately, this frameshift mutation generates a premature stop at codon 3 in exon 30. These truncated C4A and C4B gene products were confirmed through RT-PCR and sequence analysis. Among the possible genetic mechanisms that produce identical mutations is both genes, the most likely is a mutation in C4A followed by a gene conversion to generate the mutated C4B allele.

Adult↗
PubMed1987

The chemical structure of the C4d fragment of the human complement component C4.

The complete amino acid sequence of the C4d fragment (380 residues long) of the human complement component C4 is presented. Most of the sequence was determined by analysis of CNBr peptides and tryptic peptides obtained from S-carboxymethylated protein. The sequence of the amino terminal 88 residues [Campbell R. D., Gagnon J. and Porter R. R. (1981) Biochem. J. 199, 359-370] and a 106 residue polymorphic segment of C4d [Chakravarti D. N., Campbell R. D. and Gagon J. (1983) FEBS Lett. 154, 387-390] was extended. Some overlaps not provided by the protein sequence analysis were obtained from the amino acid sequence predicted by the nucleotide sequence [Belt K. T., Carroll M. C. and Porter R. R. (1984) Cell 36, 907-914]. The present protein sequence data provide information for the isolation of all the CNBr and succinylated tryptic peptides of C4d. In addition to the polymorphism previously described, two other sets of polymorphic amino acid residues at positions 153 (Ile/Ser) and 154 (Gln/Ala) have been identified. The major site of glycosylation has been shown to be an asparagine residue located in the sequence -Asn-Val-Thr- in the carboxy terminal end of C4d. A remarkable difference in the predicted secondary structure of C4d arising from one set of four polymorphic residues in a stretch of six residues and another single polymorphic residue suggests a structural basis for the origin of the different chemical reactivities of the C4 isotypes (C4A and C4B) and their serological difference in the expression of Rodgers or Chido blood group antigens. Possible non-covalent membrane attachment sites have been suggested from the hydropathy profile. Comparison of the C4d sequence with human C3, C5 and alpha 2-macroglobulin revealed extended stretches of sequence similarity (between 19 and 38% homology) with the corresponding regions of these proteins.

Amino Acid Sequence↗
PubMedDate not supplied

A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B.

Four human complement genes, which have previously been mapped between HLA-D and HLA-B on chromosome 6, have now been aligned on a 98-kilobase (kb) section of the chromosome on the basis of four overlapping cosmid clones of genomic DNA. The C2 and factor B genes, less than 2 kb apart, are about 30 kb from two C4 genes separated from each other by about 10 kb.

Chromosome Mapping↗
PubMed1990

Conversion of the C4d.2 serologic allotype of murine complement component C4 to the C4d.1 allotype by site-specific mutagenesis.

C4d.1 and C4d.2 are serologically defined allotypes of murine complement component C4. Previous studies in Shreffler's laboratory have shown that the structural difference between the two allotypes lies within a single tryptic peptide of the C4 alpha-chain and that the sequences of this fragment from the two allotypes (determined from nucleic acid sequences of genomic clones) differ only by the substitution of arginine in C4d.2 for glutamine in C4d.1. Hence this single amino acid change apparently is responsible for the rather striking serological difference between the two allotypes. To test this conclusion, we have used site-specific mutagenesis to alter the sequence of a full-length C4 cDNA that was derived from a mouse strain expressing the C4d.2 allotype. We substituted a glutamine codon for the arginine codon at the specified site and expressed both mutant and parent recombinant C4 proteins by transient transfection of COS cells. We found that an alloantiserum specific for C4d.1 reacts with the mutant protein but not the parent whereas an alloantiserum specific for C4d.2 reacts with the parent protein, as expected, but not the mutant. These results confirm that a single amino acid difference specifies the C4d.1 and C4d.2 allotypes.

Alleles↗
PubMed1996

Mouse complement component C4 is devoid of classical pathway C5 convertase subunit activity.

It has long been known that mouse C4 has unusually low hemolytic activity relative to the C4 of other mammalian species (e.g. human and guinea pig), the measurements being done in most cases using a C4-deficient guinea pig serum reagent in a one-step assay with EA. This low activity for mouse C4 previously had been attributed to "technical" difficulties such as lability of the protein during blood collection and partial species incompatibilities with guinea pig components. Recently, we presented evidence for the involvement of human C4 beta-chain residues 455-469, a putatively exposed hydrophilic segment, in contributing to a C5 binding site in the C4b subunit of the classical pathway C5 convertase, C4b3b2a. Given that there were five sequence differences between the human and mouse protein within this segment, we hypothesized that these substitutions may have compromised the C5 convertase subunit activity of mouse C4, thereby resulting in its low hemolytic activity. Using a multi-step hemolytic assay which was totally dependent upon C5 cleavage by the classical pathway, we found that mouse C4 was completely devoid of classical pathway C5 convertase subunit activity. We have been able to rule out the most obvious potential species incompatibilities (e.g. between C4mo and C5gp) as being responsible for this lack of activity. Moreover, we found that the low level of hemolytic activity of mouse C4 measured in the one-step assay can be ascribed totally to C5 cleavage, and subsequent terminal component assembly, by the alternative pathway C5 convertase, (C3b)2Bb. However, the assembly of the latter enzyme complex is dependent upon the presence of C3b molecules deposited initially via the classical pathway C3 convertase in which mouse C4b is a subunit. Finally, whereas conversion of human residues 458RP to the mouse-like sequence PL was sufficient to abrogate classical pathway C5 convertase subunit activity in human C4, the five substitutions which "humanized" the 452-466 segment of mouse C4 (corresponding to human residues 455-469) were on their own insufficient to impart this activity to mouse C4. This implies that, in addition to the 455-469 beta-chain segment of human C4, there are other regions of the molecule contributing to C5 binding which are also non-conserved between human and mouse C4.

Amino Acid Sequence↗
PubMed1993

Immunoglobulins IgG, IgA, IgM, complement C3, C4 and ferritin and transferrin levels in serum and follicular fluid in IVF patients.

Serum and follicular fluid immunoglobulin (IgG, IgA, IgM) and complement (C3, C4), as well as transferrin and ferritin concentrations were measured in 82 consecutive IVF patients (Pregnant: Group A, and non pregnant: Group B). Higher serum concentrations were observed in complement in all Immunoglobulins but IgM which was found to be significantly lower in follicular fluid in both groups. Also there were no statistically significant differences observed for transferrin and ferritin levels in either compartment or among the groups. No correlation was found for the above parameters and the in vitro fertilization outcome in terms of oocytes retrieved, fertilized and embryos implanted.

Adult↗
PubMedDate not supplied

[Complement and immunoglobulin levels in pregnant women with EPH gestosis].

The authors determined C3 and C4 complements, factor B properdin and immunoglobulins G, M and A in 20 healthy pregnant patients and in 20 patients with EPH gestosis. The analysis was performed in mothers sera, umbilical sera and amniotic fluid, and properdin factor B and IgG in urine. They used the nonfellometric technique with immunochemistry analyzer. The C3 complement was very increased in the serum of mothers with EPH gestosis, and complement C4 was slightly increased in the serum of EPH gestosis, and complement C4 was slightly in the serum of EPH gestosis, and complement C4 was slightly increased in the serum of mothers and umbilical sera. Factor B properdin was very increased in mothers sera and decreased in urine. Higher concentrations of immunoglobulin G were found in umbilical sera than in mothers sera. Increased concentrations of sera in mothers, the umbilicus and urine were observed in patients with EPH gestosis. In these patients IgM was decreased in the serum of mothers and the umbilicus. IgM was decreased in the serum of mothers and significantly increased in umbilical sera. Significant changes in patients with EPH gestosis were noted.

Complement Factor B↗
PubMed1993

Complement component C4 deficiencies and gene alterations in patients with systemic lupus erythematosus.

Deficiency of complement component C4 is considered playing a role in the genetic predisposition for systemic lupus erythematosus (SLE). The purpose of this study was to characterize the genomic alterations of the C4 and CYP21 genes in 40 caucasoid patients with SLE by C4 allotyping and by RFLP analysis. Nineteen patients (47.5%) carried C4A null alleles and eight patients (20.0%) C4B null alleles. SLE patients had more frequent C4A null alleles (47.5%) than healthy individuals (20%) (chi 2 = 10.75; P < 0.005). The commonest molecular alteration in the patients with C4A null alleles was a large gene deletion affecting both C4A and CYP21A genes. However, among the patients with C4A null alleles, 16.7% persons had no detectable C4A deletion. The non-expression of C4A gene might be due to defects at various levels of gene expression (i.e. transcription and translation). Among the patients with C4B null alleles, 62.5% persons had no detectable gene lesion, whereas 37.5% showed a C4B deletion including both C4B/CYP21A or C4B/CYP21B genes. Duplication of the C4B gene was not rare in SLE patients, as we found 15.0% of the patients with a heterozygous C4B/CY21A gene duplication. The patients typed as having C4B gene homoduplication (B1,1) demonstrated two long C4B loci, whereas heteroduplication (B1,2) displayed two short loci, therefore the type of C4B gene duplication may be related to the gene length. In conclusion, C4 deficiencies observed in 26 of the 40 SLE patients studied were very heterogeneous. In every case, the gene alteration affected both C4 and CYP21 genes.

Alleles↗
PubMed1977

The isolation and structure of C4, the fourth component of human complement.

The fourth component of complement, C4, was isolated from human serum in good yield, and in confirmation of previous reports was shown to be formed from three peptide chains, alpha, beta and gamma, with apparent mol.wts. 90 000, 80 000 and 30 000 respectively. Preparative methods are described for the isolation of the three peptide chains and their amino acid analyses reported. Component C4 contains 7.0% carbohydrate, alpha-chain 8.6% and the beta-chain 5.6%. The N-terminal amino acid sequences are given for 12 residues of the alpha-chain, eight of the beta-chain and 19 of the gamma-chain.

Amino Acid Sequence↗
PubMed1984

The complement component C4 in black Americans with type 1 (insulin-dependent) diabetes mellitus.

The complement component C4 variants C4A 4, C4B 4 and C4B Q0 were found to be significantly increased in 64 black patients with Type 1 (insulin-dependent) diabetes compared with 169 black control subjects, yielding relative risks of 3.3, 2.9 and 3.4, respectively. The increased frequencies of C4B 4 and C4B Q0 in black Type 1 diabetic patients are similar to those found in Caucasoid Type 1 diabetic patients. The data suggest that Type 1 diabetes in black Americans may be partially due to admixture of genes from whites.

Adult↗
PubMed1983

Amino acid sequence of a polymorphic segment from fragment C4d of human complement component C4.

The amino acid sequence of a segment of 106 residues of C4d has been determined by automated sequence analysis of fragments obtained by CNBr cleavage and enzymic digestion with trypsin. Polymorphism has been detected at 3 positions. Residues 9 and 12 are either valine and leucine or alanine and arginine, respectively. Residue 102 is either valine or arginine. When comparing the protein sequence with the nucleic, acid sequence [Carroll, M. and Porter, R.R. (1983) Proc. Natl. Acad. Sci. USA 80, in press] alanine or serine are found at position 98. These results may in part help to explain the inherited variants of human C4 seen on gel electrophoresis.

Amino Acid Sequence↗
PubMed1981

Treatment of human complement components C4 and C3 with amines or chaotropic ions. Evidence of a functional and structural change that provides uncleaved C4 and C3 with properties of their soluble activated froms, C4b and C3b.

Treatment of human components C4 and C3 with amines like hydrazine, ammonium hydroxide, and neutral ammonium salts or with chaotropic salts like KSCN and NaBr leads to complete loss of haemolytic activity. The pretreated components are, however, still active in formation of soluble C3 convertases. This activity pattern is reminiscent of the activities of C4 and C3 that have been activated by cleavage in the fluid phase. Indeed, the antigenic properties of pretreated C4 and C3 are similar to soluble C4b and C3b. The polypeptide chain structure of pretreated C4 and C3, is, however, identical to that of the untreated components when investigated by SDS gel electrophoresis. Pretreatment even reduces greatly the susceptibility of C4 to cleavage by C1s and of C3 to cleavage by classical and alternative pathway C3 convertases. Pretreated components have lost the ability to combine with EAC1 and EAC142, respectively; this fact explains their failure to exhibit haemolytic activity. In serum, pretreated C4 and C3 are cleaved in a manner similar to C4b and C3b. Amines and chaotropic ions cause the same functional and structural alterations, which are best explained by assumption of a conformational change. A similar transformation can also occur in C4 and C3 during preparation or storage.

Amines↗
PubMed1995

Length polymorphism of the human complement component C4 gene is due to an ancient retroviral integration.

The fourth component of the complement system, C4, is encoded by two highly homologous MHC-linked genes expressing the two isotypes C4A and C4B. A gene size polymorphism (either 22.5 or 16 kb) has been described which depends on the presence or absence of a 6.5-kb insertion in intron 9 of the C4 gene. By sequencing a C4A-specific lambda clone from a human genomic library containing the long intron 9 as well as PCR-amplified DNA containing the short intron, the DNA sequences of both introns were determined. The long and short introns have lengths of 6,787 bp and 415 bp, respectively. The sequence of the short intron is almost identical (96%) to the corresponding parts of the long intron. At position 282 of the short intron, a 6,372-bp insertion is present in the long intron which has all characteristics of a full-length endogenous retrovirus. The proviral DNA is flanked by two 6-bp target site repeats. The orientation of the proviral sequence is opposite to that of the C4 coding strand. Long terminal repeats (LTRs) of 548 bp were found at both ends of the provirus. A TATA box and an SV40 enhancer core as well as a polyadenylation signal are present in the LTR. A 5' primer binding site for lysine tRNA was identified. The strongest sequence homologies were found in comparison to human endogenous retrovirus (HERV-K): between 65-88% for gag, pol and env genes. However, a search for open reading frames in these regions indicated the presence of multiple stop codons in all three reading frames.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Composition↗
PubMed1985

Hydralazine binds covalently to complement component C4. Different reactivity of C4A and C4B gene products.

Long-term treatment with hydralazine is sometimes associated with deposition of immune complexes and development of systemic lupus erythematosus (SLE) as an adverse side-effect. Hydralazine inhibits the covalent binding reaction of the complement protein C4. We show that when hydralazine inhibits C4, it becomes covalently bound to the polypeptide chain containing the active site thiol ester. C4 is encoded at 2 adjacent polymorphic loci, C4A and C4B, within the major histocompatibility complex. We show that hydralazine binds more efficiently to the C4A than to the C4B gene product and suggest that C4 type may predispose patients to hydralazine-induced SLE.

Complement C4↗
PubMedDate not supplied

[In-vivo activation of the 4th component of the complement system (C4) in premature and term infants with generalized bacterial infections].

The concentrations of the complement components C3 and C4 and their activation products C3dg and C4d were determined in EDTA-stabilized serum of 25 premature and term infants. EDTA plasma and EDTA serum obtained from 30 normal blood donors were used as controls. According to clinical, laboratory and/or microbiological findings, six of the 25 children had infections. The mean scatter range of the C3 and C4 values was from 30% (in the 30th week of pregnancy) to 80% (in term infants) of the normal value for adults. In all the children, irrespective of gestational age, the C3dg concentrations were of the same order of magnitude as in healthy adults. As regards the C3, C4, and C3dg values, there was no difference between the newborns with and without infections. The C4d values of the newborns without infections, on the other hand, (range 0.1-1.4 mg/dl, mean 0.8 mg/dl, n = 19) were significantly lower than those of the newborns with infections (range 1.3-2.4 mg/dl, mean 1.95 mg/dl, n = 6). Observation of the course and comparison with CrP showed that elevated C4d values may occur earlier. In the authors' view, these findings indicate that in bacterial infections of premature and term infants the fourth complement component is activated, while the extent to which the third complement component is involved in the activation process is not measurable. Further studies are needed to establish whether early diagnosis of neonatal sepsis can be improved by determining C4d.

Bacterial Infections↗
PubMed1991

Quantitative and antigenic differences in complement component C4 between American blacks and whites.

A population of 98 healthy Black Americans was studied in order to determine normal ranges for total C4, C4A and C4B. Mean total C4 in Blacks measured by an enzymelinked immunoassay (EIA) was 44 +/- 12.8 mg/dl which was significantly different (p less than 0.001) from Caucasian levels of 31.7 +/- 11.5 mg/dl. The difference in total C4 was due to increased levels of C4B in Blacks (means = 24.4 mg/dl) as compared to Whites (means = 15.7 mg/dl; p less than 0.001). These results remained significantly different even when 8 samples having the C4A 91 phenotype were excluded. Since EIAs using monoclonal antibodies with Ch 1 specificity may yield false results, C4 allotyping is recommended when quantitating C4A and C4B levels in Blacks.

Alleles↗