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Three structural forms of C7 have been distinguished by isoelectric focusing. They are the products of three co-dominantly expressed alleles at an autosomal locus. The C7 locus is close to that for C6, but is not close to the HLA complex.
The polymorphisms of the B subunit of coagulation factor XIII (F13B), plasminogen (PLG), complement C6, C7, factor B (BF) and factor I (IF) were studied among 21 unrelated Japanese patients with primary varicose veins (PVV) by isoelectric focusing followed by immunoblotting. The allele frequencies for F13B*2 and IF*A in PVV patients were significantly higher (F13B*2, p = 0.0047; IF*A, p = 0.0006) than those in healthy controls (n = 60). Significant associations of F13B 2 allotype [p = 0.0220, relative risk (RR) = 13.9] and IF A allotype (p = 0.0006, RR = 10.0) with PVV were observed; however, no significant association of PLG, C6, C7 or BF allotype with the disease was found.
A 14-year-old boy had persistent haematuria along with complete C7 deficiency. No significant changes in glomeruli and tubules were found in a renal biopsy specimen by light microscopy and immunofluorescence gave negative results for immune deposits. Electron microscopic examination demonstrated an attenuation of the glomerular capillary basement membrane without lamination and a diagnosis of thin basement membrane disease was made. It would be difficult to conclude that patients with C7 deficiency were predisposed to develop glomerulonephritis caused by immunologic aberrations. A family study failed to provide evidence of an association of C7 deficiency and thin basement membrane disease.
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The results of reference typing for C7 are presented and discussed. It appears that the present literature is using consistent nomenclature except that it was not possible to distinguish between the European C7-3 allele and Japanese C7-6. Oriental populations have both a higher frequency of variants and a greater variety of variants than Caucasian populations. Some samples with complex patterns defied classification, and it is speculated that these may be from persons with duplicated C7 genes. It is recommended that no change to the present system of nomenclature be made before a more detailed molecular understanding of the system is achieved.
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The molecular architecture of human complement component C6 was elucidated at several levels of structural organization. The entire primary structure of C6 was determined by sequencing C6 cDNA that was cloned from a human liver lambda gt11 library. The polypeptide chain of C6 contains 913 amino acids. The protein is homologous with the other terminal components of complement, C7-C9. Specifically, C6 has 29% of its residues identical with C7, and 55 of the 56 cysteines found in C7 match those in C6. The C6 polypeptide chain is cross-linked by 32 disulfide bonds, and most of the cysteines are located in short (34-77 amino acids) discrete segments that exhibit homology with a wide variety of other proteins such as thrombospondin, the low density lipoprotein receptor, epidermal growth factor, and complement factors H and I. C6 is a glycoprotein, and it has two oligosaccharide groups attached to asparagines located near the amino and the carboxyl termini of the molecule. The organization of secondary structural elements in C6 was elucidated using circular dichroism spectroscopy and an empirical method based on sequence analysis. C6 has an estimated 12% alpha-helix, but is comparatively richer in beta-sheet (29%) and beta-turns (21%). Most of the predicted alpha-helical structure resides in a portion of the polypeptide chain that is free of cysteine and which shares homology with C9 and perforin. The tertiary structure of the C6 molecule was visualized by transmission electron microscopy; it has a sickle shape with dimensions of 144 x 66 A. The combined results are discussed and comparisons made with the other late acting components of complement and perforin.
By routine screening of sera, a subject was discovered who showed a sub-total deficiency of C6 and C7. No clinical disease was associated with this deficiency which was transmitted through the subject's family as a single genetic characteristic, the C6 deficiency being associated with a silent allele at the structural locus. The propositus was found to have low quantities of an abnormal C6 which was both antigenically deficient and smaller in size than normal C6 (110,000 daltons compared with 140,000 daltons) and small quantities of apparently normal C7. It is concluded that the most likely explanation for this defect is that the subject has a structural mutation in his C6 gene which produces hyopsynthesis not only of C6 but also of the closely linked gene for C7. These findings suggest the possibility that C6 and C7 may function as a single genetic unit and that the primary transcript copied from the genome includes information for both proteins.
A new reliable and reproducible technique for the simultaneous determination of C6 and C7 types is presented, which employs double replica electroblotting after isoelectric focusing. It permitted clear discrimination of both C6 and C7 components, and the patterns were nearly comparable to those demonstrated separately. The population data obtained by this new technique fitted the genetic hypothesis. The present double replica electroblotting method was successfully applied to the combined phenotyping of C6 and C7 from bloodstains which were stored at room temperature for up to 4 weeks. The method is quite suitable for medicolegal examination of bloodstains particularly for the saving in the amount of sample.
Activation of C in C8-depleted serum results in the formation of a soluble complex containing C5, C6, and C7. The complex has an electrophoretic mobility of an alpha-globulin, an s-rate of 18.5S, and a m.w. of 668,000 daltons. This complex was isolated and upon SDS polyacrylamide gel electrophoresis it was found to contain, in addition to C5b, C6 and C7, an 88,000 dalton glycoprotein. The protein was identified as the band V protein of the soluble C5b-9 complex. It is referred to as SIIIs-protein, or S-protein. Since the S-protein does not bind to C5b-6, it is concluded that it is incorporated during the fusion of C5b-6 with C7. The SC5b-7 complex exhibits the same neoantigen as the SC5b-9 complex, but compared to the C5b-6 complex it appears to contain an additionally qualitatively distinct neoantigen.
In a comparative study the hemolytic activity of C3, C5, C6, C7, C8, C9 and the C3 proactivator (C3PA) were measured in sera of 22 patients with chronic membrano-proliferative glomerulonephritis (CMPGN), 15 patients with idiopathic nephrotic syndrome, 10 patients with systemic lupus erythematosus, 7 patients with anaphylactoid purpura and 10 patients with acute poststreptococcal nephritis. In CMPGN, C3, C5, C6, C7 and C8 were low in the majority of the patients, whereas C9 and C3PA were depressed only in 21% and 11% of the patients, respectively. By contrast, C3PA and C8 showed striking depressions in the idiopathic nephrotic syndrome. In lupus erythematosus, all the C factors, including C3PA were found to be low with the exception of C9, which was normal in 80% of the patients studied. C3, C5, C6 and C7 were found to be depressed in acute glomerulonephritis; C8 and C9 titers were normal. In all patients studied with anaphylactoid purpura, CH50 and C3 titers were elevated markedly.
Records of 17 patients who had two or more attacks of pyogenic meningitis were collected from eight centres in the United Kingdom for retrospective analysis. Thirteen patients had intracranial abnormality; of seven with head injury five produced cerebrospinal fluid rhinorrhoea. The first of the 28 attacks seen in these occurred between a few weeks and 12 years of the head injury. Pneumococci were identified in 25 episodes in cerebrospinal fluid. Of six patients without a history of head injury, one had 'spontaneous cerebrospinal fluid rhinorrhoea' and five had pathological changes of the ear. Various organisms were found in the cerebrospinal fluid during the 12 attacks in these five. Four of the 17 patients had primary complement deficiency (C7, C5, C4 and C3b inhibitor); 10 (possibly 11) of 16 attacks in these cases were due to Neisseria meningitidis. Routine radiological investigations including computerized tomography did not always identify the abnormality; radioactive cisternography can help to establish cerebrospinal fluid leak. All 58 episodes of pyogenic meningitis in these 17 patients with different underlying disease responded to conventional treatment with antibiotics without mortality and without undue morbidity. Surgical procedures in intracranial disease had variable success. Correction of complement deficiency is not practical at present. In some patients prophylaxis with antimicrobial drugs is the only method of preventing future attacks.
The genetic variation of the human plasma proteins ORM1, C6, C7 and APO C-II was investigated by isoelectric focusing followed by immunoblotting in populations from mainland Italy and Sardinia. The frequencies of ORM1*1 were 0.621 and 0.564, while those of C6*A were 0.657 and 0.706 on mainland Italy and in Sardinia, respectively. In the Roman sample, 8 heterozygotes with C6 variant alleles were encountered, while none were observed in Sardinians. For C7 and APO C-II a number of heterozygotes with the rare alleles C7*2 and APO C-II*2 were found, but their frequency did not reach polymorphic levels in either population. The two populations showed a significant difference in the gene frequencies distribution for ORM1.
Earlier studies have shown that sequential treatment of resealed erythrocyte ghosts with C5b6, C7, C8, and C9 leads to insertion of hydrophobic peptides from these complement proteins into the membrane and assembly of transmembrane channels. The number of molecules of each of the proteins required for assembly of the membrane-associated channel structure was evaluated by measuring the quantitative relationship between the doses of the individual proteins and the release of two trapped markers, sucrose and inulin, from ghosts after channel formation. The incubation period was sufficient to attain equilibrium of marker distribution between the ghosts and the extracellular fluid. Two markers of different size (sucrose and inulin, 0.9 and 3 nm molecular diameter, respectively) were used in order to develop information on the molecular composition of small and large channels, respectively. We found that participation of C5b6, C7, and C8 in channel formation displayed one-hit characteristics, regardless of marker size. By contrast, the participation of C9 was one-hit with respect to the sucrose marker, whereas with respect to the inulin marker the C9 reaction was multi-hit. Our results are compatible with the view that these markers are released through a channel structure in the membrane that is a monomer of C5b--9 of the composition C5b61 C71C81C9n, in which n = 1 for channels permitting passage of sucrose and n = 2 for channels allowing transit of inulin.
190 Punjabis (Hindus and Sikhs) of Chandigarh and 152 Hindus of Jodhpur (Rajasthan) were examined for six genetic markers, four of which (APO C-II, C6, C7 and FXIIIA) were not studied before in Asiatic Indians. For APO C-II and C7 only the common phenotype was found in a total of 229 and 99 subjects, respectively. For the remaining four markers the two samples were pooled since the gene frequency estimates were not significantly different: FXIIIA*2 = 0.205 +/- 0.016; C6*B = 0.366 +/- 0.037; PGM1*2 = 0.247 +/- 0.017; PGD*C = 0.041 +/- 0.008. These data may contribute to evaluate the extent of the Mongoloid genetic admixture into the Caucasoid gene pool of the Punjab and Rajasthan Hindu population.
Genetic polymorphism of C6 in the Japanese population has been described using polyacrylamide gel isoelectric focusing electrophoresis followed by the electrophoretic blotting technique, and haplotype analysis between C6 and C7 has also been investigated. In 565 plasma samples five different common patterns and three rare variant patterns were observed, and these were controlled by autosomal codominance at a single locus with three common and one rare alleles. These alleles were designated C6*B, C6*A, C6*B2, and C6*M, and gene frequencies were estimated to be 0.50265, 0.43186, 0.06018, and 0.00531 for C6*B, C6*A, C6*B2, and C6*M, respectively. It is noteworthy that C6*B2 has a polymorphic frequency in the Japanese population. The distribution of phenotypes fitted the Hardy-Weinberg equilibrium. Two combinations between C6 and C7 alleles, namely C6B-C7B and C6M-C7B, were shown to be in significant positive linkage disequilibrium. The presence of allelic combinations showing linkage disequilibrium suggests the close proximity between the C6 and C7 loci.
Light-scattering intensity was shown to be a reliable, direct, and quantitative technique for monitoring the assembly of the membrane attack complex of complement (proteins C5b-6, C7, C8, and C9) on small unilamellar phosphatidylcholine vesicles. The assembly on vesicles occurred in a simple fashion; complexes of C5b-7 bound noncooperatively to the vesicles, and final assembly of C5b-9 did not induce vesicle aggregation or fragmentation. When C5b-6 and C7 were mixed in the presence of vesicles but at molar protein/vesicle ratios of less than 1, there was quantitative binding of C5b-7 to the vesicles with no concomitant aggregation of C5b-7. If C7 was added at a slower rate, quantitative binding was obtained at molar C5b-7/vesicle ratios of up to 5. The latter observations (a) were consistent with the proposal that C5b-7 aggregation and membrane binding were competitive events and (b) defined conditions under which light-scattering intensity measurements could monitor C5b-9 assembly on vesicles without contribution from the fluid-phase assembly. The C8/C5b-7 ratio in the phospholipid-C5b-8 complex was 0.97 +/- 0.12, and the maximum ratio of C9/C5b-8 in the final complex was 16.2 +/- 2.0. One C9 molecule associated rapidly with each phospholipid-C5b-8, followed by slower incorporation of the remaining C9 molecules. The initial velocity of the slow phase of C9 addition was easily saturated with C9 and gave an activation energy of 37 kcal/mol. This was identical with the value measured for the analogous process in the fluid-phase assembly.(ABSTRACT TRUNCATED AT 250 WORDS)
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