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PubMed1992

Aberrant splicing caused by the insertion of the B2 sequence into an intron of the complement C4 gene is the basis for low C4 production in H-2k mice.

The serum level of the fourth component of complement (C4) in mice bearing the H-2k haplotype is only 1/10 to 1/20 of that of non-H-2k mice. We have analyzed C4 cDNA clones from B10.BR(H-2k) mouse liver and found aberrant C4 cDNA which contained a 200-base pair (bp) insertion between the exon 13 and exon 14 encoded sequences in addition to the normal C4 cDNA. The 5' 148 bp and the 3' 52 bp of this insert were derived from the B2 sequence, the short interspersed repeats of mouse genome, and the central part of intron 13, respectively. Sequence analysis of intron 13 of the C4k gene showed the presence of a complete copy of a B2 consensus sequence. The structure of aberrant C4 mRNA indicated that the possible 3' splice site in the B2 sequence and the cryptic 5' splice site in intron 13 were used. Both the insertion of the B2 sequence into intron 13 and the presence of aberrant mRNA in the liver were specific to H-2k-bearing mice, suggesting that the aberrant splicing due to the B2 insertion is the basis for low C4 expression in H-2k mice.

Animals↗
PubMed2002

Choroidal vascular occlusion in a child with a connective tissue disease and complement C4 deficiency.

OBJECTIVE: To report the histopathologic findings in the eyes of a patient with a connective tissue disease and complement deficiency. DESIGN: Human postmortem ocular histopathologic study. INTERVENTION: A 15-year-old female died from complications of a connective tissue disease of uncertain etiology, particularly acute respiratory distress syndrome. Abnormalities seen in the eyes at autopsy were consistent with complement activation, granulocyte aggregation, and leukocyte embolization. MAIN OUTCOME MEASURES: Both eyes were examined by light microscopy. RESULTS: Some choroidal vessels were occluded by platelet-fibrin thrombi and occasionally by aggregates of granulocytes and fibrin. Serous retinal detachment involving the macula and peripheral retina was present in both eyes. CONCLUSIONS: This is a report of the ocular histopathologic findings in a patient with connective tissue disease and complement C4 deficiency. The light microscopy findings were consistent with complement activation with granulocyte aggregation and leukocyte embolization and may represent another mechanism to explain the clinical findings in patients with connective tissue disease, particularly systemic lupus erythematosus.

Adolescent↗
PubMed1997

Polymorphism of the fourth component of complement (C4) and three clinical pictures of hepatitis B virus infection in children.

The fourth component of complement (C4) phenotype and allele frequencies were studied in 3 groups of unrelated children affected with hepatitis B virus (HBV) infection (25 with glomerulonephritis (GN), 39 with chronic active hepatitis (CAH), 24 with Gianotti-Crosti syndrome (GS-S)) and in 100 unrelated healthy individuals (H). Ten phenotypes in GN, 14 in CAH, 10 in GC-S and 23 in H were found. Some rare phenotypes appeared in the individual cases of ill children. Statistical analysis was performed by chi-square test. Each group was compared to the others. We found significantly higher frequency of the A3B2,Q0 phenotype in CAH than in H as well as significant increase of the A x 4 gene frequency in GC-S as compared to H. However, these events could be caused by limited number of tested patients. We suspect that the association between C4 alleles and immune-complex diseases, studied here, does not rather exist.

Alleles↗
PubMed1993

HLA-DQ, DR and complement C4 variants in systemic lupus erythematosus.

We have defined HLA-DQA, DQB, DR and complement C4 variants in 92 subjects with SLE and 73 controls. Subjects with SLE showed an increased frequency of HLA-DQA*0501 (P < 0.01 corrected, odds ratio (OR) = 4.97; 95% C.I. = 2.52-9.81), DR3 (P < 0.001, OR = 3.18; 95% C.I. = 1.67-6.04) and C4A*Q0 (P < 0.05, OR = 1.91; 95% C.I. = 0.999-3.65) vs controls. These increases were particularly marked in those subjects positive for antibodies to both Ro and La. HLA-DQB*0501 (P < 0.01 corrected, OR = 0.03), DQA*0101 (P = 0.0012 uncorrected, OR = 0.23) and DR7 (P = 0.0018 uncorrected, OR = 0.28) were decreased in frequency in SLE. SLE patients with disease onset prior to age 30 yr were more likely to possess a DR3-bearing haplotype (P < 0.05 corrected) than those with onset after age 30 yr. No significant associations were found in patients with circulating antibodies to double-stranded DNA, Ro alone, U1 RNP, Sm or in those SLE patients with renal disease or vasculitis. The different associations found in different clinical and immunological subsets of SLE support the concept that SLE contains a variety of immunogenetic subgroups. Analysis of the associations between SLE and DR3, DQA*0501 and C4A*Q0 using the empirical logistic test suggests that the association of SLE with HLA-DQA*0501 is likely to be primary to the associations with both DR3 and C4A*Q0 (P < 0.001). Our results therefore raise the possibility that genes within the HLA-DQ region may have a direct effect upon susceptibility to SLE.

Adolescent↗
PubMed1986

Sequence comparison of alleles of the fourth component of complement (C4) and sex-limited protein (Slp).

cDNA clones specific for the fourth component of complement (C4) and its androgen-regulated isotype, sex-limited protein (Slp), have been isolated from two mouse haplotypes (H-2d and H-2w7) that show differential C4 activity and differential regulation of Slp. Clones were first isolated using a cDNA probe enriched by subtractive hybridization. Subsequent screening has resulted in cDNAs spanning the entire C4d mRNA, as well as much of C4w7, Slpw7 and a short region of Slpd. The cDNAs for C4 and Slp show extensive sequence homology, but can be distinguished using oligonucleotide probes synthesized to regions of greatest sequence divergence. Sequence differences between C4 and Slp indicate structurally important features of C4 that have been altered in Slp such that Slp is unable to participate in the complement pathway. Of the few nucleotide differences between C4d and C4w7, a single base change resulting in one less glycosylation site in the C4w7 alpha chain could account for its 4-fold reduced hemolytic efficiency. Sequence comparison of multiple alleles of C4 and Slp indicates that possible gene conversion events occurred in the H-2w7 strain that has multiple Slp genes.

Alleles↗
PubMed1988

C3 and C4 complement components and acute phase proteins in late pregnancy and parturition.

To determine whether changes in complement or acute phase proteins can predict onset of labour, complement components C3 and C4, alpha-1-antitrypsin, and alpha-1-acid glycoprotein were measured serially in the third trimester of pregnancy and throughout labour in 11 women. C-reactive protein (CRP) concentration, C3 conversion products, and factor B activation was studied in five pregnancies one week before delivery, during labour, and six weeks after delivery. C3, C4, and CRP concentrations were unchanged and there was no evidence of complement conversion, either immediately before or during labour, by the classical or alternative pathways. A wide variation among subjects but a small variation within subjects for all proteins assayed was noted. It is important to use serial rather than cross sectional biochemical data when determining normal physiological patterns in pregnancy. The proteins measured have no predictive value in the timing of the onset of normal labour.

Adult↗
PubMed1991

Increased frequency of complement C4 'null' alleles in recurrent spontaneous abortions.

Typings for major histocompatibility antigens HLA A, B, C and DR and for complement C4A, C4B and factor B were performed for 59 Finnish couples experiencing at least three consecutive recurrent spontaneous abortions (RSA). Forty-one of them were primary abortion (PA) couples with no children and 18 were secondary abortion (SA) couples who had one or two children before abortions. HLA sharing in A and B loci was slightly but significantly increased (15%, P less than 0.05) among RSA couples compared to the controls, as was DR sharing among SA couples compared to PA couples (50% versus 22%, P less than or equal to 0.05). The most interesting new finding, however, was the statistically significant increase of complement C4 functionally silent, i.e. C4 'null', alleles in RSA couples. C4 is a duplicated gene and its products differ in their functions in the complement cascade. C4A null alleles were equally increased in PA wives and in PA husbands (32%, P less than or equal to 0.05) compared to the controls (18%) and C4B null alleles in SA wives (56%, P less than or equal to 0.05) and in SA husbands (50%) compared to the controls (29%). Therefore, the offspring of RSA couples have a significantly increased risk of inheriting several null alleles. The majority, 95% (P less than 0.001) of PA couples and 83% of SA couples, had at least one C4A or C4B null in their phenotypes compared to 66% among Finnish controls.

Abortion, Habitual↗
PubMed1981

Evidence that the fourth component of complement (C4) is carried on a high proportion of normal guinea-pig B lymphocytes.

The fourth component of complement (C4) has been demonstrated on the cell membrane of guinea-pig B lymphocytes isolated from blood, lymph nodes and spleen. In lymph nodes, at least, the C4-positive cells also carry receptors for C3 and most bind IgG-Fc. Few, if any, T lymphocytes have detectable C4. Resynthesis of cell-surface C4 could not be shown following in vitro culture of lymphocytes stripped of C4 by proteolytic enzymes, and it is likely that the C4 is passively acquired in vitro from tissue fluids, possibly by a mechanism similar to that involved in the binding of C4 (Chido and Rodgers determinants) to human erythrocytes.

Animals↗
PubMed1993

Identification of a surface structure in the fourth component of human complement, C4, which becomes hidden upon activation by C1(-)s.

Treatment of complement component C4 with C1(-)s and methylamine induces a series of conformation changes such as to generate functional binding sites. A monoclonal antibody (mAb), Al 121/6, which does not inhibit the haemolytic activity of C4 was found to bind to native C4 and C4d, but not to C4b and methylamine-treated C4, unless these C4 derivatives were denatured. These results suggested that a linear epitope for mAb Al 121/6 in the C4d domain is originally located at the surface of C4 and becomes hidden as a result of conformational changes induced by C1(-)s or methylamine treatment. The hidden linear epitope was exposed again upon further cleavage of C4b into C4c and C4d. Trypsin digestion of C4d and its chemical modification with phthalic anhydride suggested that the epitope is located at the C-terminal 13 kDa region of C4d and that lysine residues are involved in the epitope. There is a single lysine residue at 1259 in the 13 kDa C-terminal side of C4d and the synthetic undecapeptide Leu1254-Asp1264 was found to inhibit the binding of C4 to mAb Al 121/6, suggesting that the epitope for mAb Al 121/6 is involved in the sequence. The N-terminal portion of the peptide is partly overlapping, with a highly hydrophobic amino acid sequence spanning residues Ala1249-Leu-Leu-His-Leu-Leu-Leu1255. The surface hydrophobicity of C4 has been reported to decrease upon treatment with C1(-)s and methylamine. So it appears that the hydrophobic sequence spanning Ala1249-Leu1255 may be hidden, together with the linear epitope, into the inner region of C4 upon treatment with C1s and methylamine.

Antibodies, Monoclonal↗
PubMed1990

HLA class I-, complement C4- and 21-hydroxylase probes in the genetic analysis of 21-hydroxylase deficiency.

In order to develop an optimal strategy for the prenatal diagnosis of steroid 21-hydroxylase (EC 1.14.99.10) deficiency, we investigated 16 affected families with salt wasting syndrome. Genomic DNA derived from peripheral white blood cells was digested with 6 different restriction enzymes. Hybridisation was carried out with DNA-probes of the HLA class I region, the 21-hydroxylase- and the complement C4 genes. All the families were informative in at least three different loci. Twelve out of the 16 families were informative by neutral polymorphisms or disease related variants of the 21-hydroxylase gene or the adjoining C4 locus. The reliability of prediction in these cases exceeded 99%. The remaining 4 families were informative only in the HLA class I region, tantamount to a reliability of prediction of about 98%. In none of the cases did we have to fall back on semiquantitative gene dose assessments. We further describe new polymorphisms in the 21-hydroxylase region for the enzyme Pvu II and EcoR V.

Adolescent↗
PubMed1986

Identification of the 5'-flanking regulatory region responsible for the difference in transcriptional control between mouse complement C4 and Slp genes.

To elucidate the molecular basis underlying the difference in the mode of gene expression between mouse complement C4 (constitutive) and sex-limited protein (Slp) (testosterone-regulated), we compared nucleotide sequences and transcriptional regulatory activities of the 5'-flanking regions of these two genes. Although the two sequences showed a high degree of overall homology (95%) up to 1.9 kilobases (kb) upstream from the transcription initiation site, the Slp sequence lacked a 31-nucleotide segment containing ACACCC repeats and a 60-nucleotide segment containing ACAC repeats, which are present, respectively, 1.6 kb and 200 base pairs (bp) upstream from the transcription initiation site of the C4 gene. When assayed in human hepatoma-derived HepG2 cells, the 1.8-kb 5'-flanking DNA fragment of the C4 gene demonstrated strong transcriptional activity, whereas the corresponding DNA fragment of the Slp gene showed only negligible activity. By progressive deletion experiments, it was shown that the difference in the constitutive transcriptional activity of the C4 and Slp genes was accounted for by the presence or absence of the positive regulatory domain located between 1700 bp and 400 bp upstream of the transcription initiation site.

Acetyltransferases↗
PubMed1992

Major histocompatibility complex located complement C4 and steroid 21-hydroxylase gene rearrangements in couples with recurrent spontaneous abortions.

Major Histocompatibility Complex (MHC) class III located complement C4 and steroid 21-hydroxylase (21OH) genes, which form various deletion and duplication units, were studied by TaqI Restriction Fragment Length Polymorphism (RFLP) in 58 Finnish couples who suffered recurrent spontaneous abortions (RSA). The gene rearrangements found in the RSA couples did not differ from those in the controls.

Abortion, Habitual↗
PubMed1986

Complete nucleotide and derived amino acid sequences of sex-limited protein (Slp), nonfunctional isotype of the fourth component of mouse complement (C4).

The nucleotide sequence coding for sex-limited protein (Slp), the testosterone-regulated isotype of the fourth component of mouse complement (C4), has been determined from cloned genomic DNA and cDNA fragments. The complete deduced amino acid sequence for the single chain precursor protein of Slp (pro-Slp) consists of 1716 residues. The mature beta, alpha, and gamma subunits contain 654, 763, and 291 amino acids, respectively. One potential carbohydrate attachment site is predicted from the beta-chain, five for the alpha-chain, and none for the gamma-chain. From the comparison with the mouse C4 sequences, an extensive overall sequence homology, 96.0% in nucleotides and 94.2% in amino acids, is observed. Only one deletion/insertion event is recognized between C4 and Slp sequences: three residues near the Cls cleavage site are deleted from Slp. The distribution of cysteine residues is completely conserved between pro-Slp and pro-C4.

Amino Acid Sequence↗
PubMed1995

Association between circulating immune complexes, complement C4 null alleles, and myocardial infarction before age 45 years.

One hundred patients who had survived a myocardial infarction before the age of 45 years and 90 age- and sex-matched healthy individuals were investigated for circulating immune complexes (CICs) and the presence of complement C4 null alleles (C4Q0). CICs were found in increased concentrations in 20% of patients and 6.7% of control subjects. Patients and control subjects had the same prevalence of C4Q0. CICs were present in all patients and in 36% of the control subjects homozygous for C4Q0. Patients and control subjects heterozygous for C4Q0 had CICs in 71% and 0%, respectively. The high prevalence and a high concentration of CICs were particularly associated with C4A*Q0. Patients homozygous for C4A*Q0 had concentrations of LDL that were lower than found in other patients. The increased concentration of CICs associated with genetic deficiencies of the complement factor C4 might thus be an additional etiological factor for the development of chronic vascular damage and premature myocardial infarction.

Adult↗
PubMed1996

Comparative analysis of the disease-associated complement C4 gene from the HLA-A1, B8, DR3 haplotype.

Complement component C4 is an important protein of the classical, or antibody-mediated pathway of complement activation. Human C4 is located within the central region of the major histocompatibility complex on chromosome 6. Partial C4 deficiency has been associated with an increased susceptibility to immune complex disease. The strongest association with partial C4 deficiency is with systemic lupus erythematosus (SLE) and has been shown in most racial groups studied. Interestingly, Caucasian population studies have demonstrated an increased prevalence of C4A null alleles in SLE patients, in particular in association with the haplotype HLA-A1, B8, BfS, C4AQ0, C4B1, DR3. To investigate whether the C4 gene on this haplotype had any structural irregularities which may explain disease association, we sequenced the entire C4B gene from this haplotype. The results revealed that the gene encoded on the disease-associated haplotype carried major structural differences (when compared to C4A3) at the exonic level only in the C4d region. A high degree of conservation in both the 5' and 3' untranslated regions imply that disease associations will not be due to differential C4 expression as a result of regulatory differences between C4 genes. It appears likely that protein clearance mechanisms may account for the altered levels of C4 seen between different isotypes.

Amino Acid Sequence↗
PubMed1989

Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21-hydroxylase and complement C4 gene repeats in 21-hydroxylase deficiency haplotypes.

The human steroid 21-hydroxylase gene, CYP21B, and its closely homologous pseudogene, CYP21A, are each normally located centromeric to a complement C4 gene C4B and C4A respectively, in an organization suggesting tandem duplication of a CYP21 + C4 unit. Such an organization has been considered to facilitate gene deletion and addition events by unequal crossover between the tandem repeats. However, the large size (approximately 30 kb) of the individual CYP21 + C4 repeat units together with the difficulty in identifying reliable CYP21A- and CYP21B-specific markers has prevented direct monitoring of gene organization on individual haplotypes by conventional Southern analyses. In the present investigation we have sought to clarify the CYP21 and C4 gene organization in members of 32 British 21-hydroxylase deficiency families by employing additional experimental approaches, notably a long-range restriction mapping approach, which permits assessment through a VNTR type of analysis, of the number of CYP21 and C4 units on individual haplotypes. Our results show that there is a very high frequency (33%) of 21-hydroxylase deficiency haplotypes where functional CYP21B gene sequence has been removed as a consequence of CYP21 + C4 gene deletion while several haplotypes show evidence of gene addition. In each case that we have investigated the gene deletion and gene addition haplotypes differ in length from conventional haplotypes by integral multiples of approximately 30 kb, which strongly supports the involvement of unequal crossover mechanisms. Additionally, the comparatively frequent occurrence of CYP21 fusion genes which contain both CYP21A- and CYP21B-associated markers is suggested by the combined data from Southern analyses, long-range restriction mapping and characterization of selected regions of CYP21 genes which have been amplified in vitro.

Adrenal Hyperplasia, Congenital↗
PubMed1984

Inherited incomplete deficiency of the fourth component of complement (C4) determined by a gene not linked to human histocompatibility leukocyte antigens.

We have studied a family in which the proband had systemic lupus erythematosus and selective incomplete deficiency of the fourth component of complement (C4) (2-5% of the normal level). An additional six healthy family members also had low C4 levels (2.4-24.1% of normal) but no evidence of lupus. This form of inherited C4 deficiency differs from that in previously reported families in that inheritance was autosomal dominant (rather than recessive), C4 levels were markedly reduced (but not undetectable), and there was no linkage to HLA, BF, or C4 structural loci, all known to be within the major histocompatibility complex.

Adult↗