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PubMed1998

Complement C6 deficiency protects against diet-induced atherosclerosis in rabbits.

Low-density lipoprotein (LDL) can be transformed to an atherogenic moiety by nonoxidative, enzymatic degradation. Enzymatically degraded LDL induces macrophage foam cell formation, provokes release of cytokines, and also activates complement. To determine whether complement activation may contribute to atherogenesis, 6 pairs of homozygous C6-deficient rabbits and their non-C6-deficient heterozygous siblings were fed a cholesterol-rich diet for 14 weeks. Cholesterol levels and plasma lipoprotein profiles of the animals in the C6-competent and C6-deficient groups did not significantly differ, and the high density lipoprotein and LDL cholesterol ratios at the end of the experiment were 0.07+/-0.01 and 0.08+/-0.01 (SEM), respectively. However, differences in atherosclerotic plaque formation were discernible macroscopically, with extensive aortic lesions being visible in all C6-competent animals and absent in all C6-deficient animals. Aortas were sectioned from thorax to abdomen, and 10 sections were stained from each aorta. Quantification of atherosclerotic lesions and lumen stenosis with the use of computer-based morphometry documented a dramatic protective effect of C6 deficiency on the development of diet-induced atherosclerosis. We conclude that the terminal complement sequence is centrally involved in atherosclerotic lesion progression.

Animals↗
PubMed1982

Characterization of human complement components C6 and C7.

Human complement components C6 and C7 have been purified and characterized. Component C6 is a single-chain plasma protein of mol. wt 104,800 containing 3.8% carbohydrate and it has alanine as the amino terminal residue. Component C7 is a single-chain plasma protein of mol. wt 92,400 containing 6.4% carbohydrate and it has serine as the amino terminal residue. Primary sequence analysis failed to provide evidence of homology between these two proteins.

Amino Acid Sequence↗
PubMed1989

Structural homology of complement protein C6 with other channel-forming proteins of complement.

The amino acid sequence of the amino-terminal half of the complement protein C6 has been found to show overall structural homology with the homologous regions of the channel-forming proteins C7, C8 alpha, C8 beta, and C9. In addition, two specific cysteine-rich segments common to the amino-terminal regions of C7, C8 alpha, C8 beta, and C9 also occur in their expected positions in C6, suggesting functional significance. Two cDNA clones encoding C6 were isolated from a human liver library in the bacteriophage vector lambda gt11. The predicted protein sequence contains an apparent initiation methionine and a putative signal peptide of 21 residues, as well as a site for N-glycosylation at residue 303. The sequence of the C6 protein reported here has 47-52% similarity with C7, C8 alpha, C8 beta, and C9, as well as 31-38% similarity with thrombospondin, thrombomodulin, and low density lipoprotein receptor. The sequence data have been interpreted by using computer algorithms for estimation of average hydrophobicity and secondary structure.

Amino Acid Sequence↗
PubMed1995

Active Heymann nephritis in complement component C6 deficient rats.

The mechanisms of renal injury that result in proteinuria in active Heymann nephritis (AHN) remain unclear, though data suggest that in analogy of the passive form of the disease the membrane attack complex C5b-9 may be involved. AHN was induced in an inbred strain of PVG/c-rats that are totally deficient in the C6 component of complement and are unable to form the lytic C5b-9 complex, as well as in non-complement deficient PVG/c+ rats that are immunologic identical to the deficient strain. In both groups of animals comparably high titers of anti-Fx1A autoantibodies were found after three weeks and persisted at 40 weeks. Proteinuria was also similar in both groups, and was first evident at six weeks. High levels of urinary protein, ranging from 200 mg/24 hr to 500 mg/24 hr, were found after 10 weeks and persisted up to one year. Renal biopsy findings at various times post-immunization were identical in both groups, including immunofluorescence staining for Ig and C3 deposits, and also EM findings of subepithelial electron-dense deposits were not different. The injection of heterologous rabbit complement, that partially and temporarily restored the CH50 activity in PVG/c- rats did not alter or hasten the disease. Long-term follow-up showed that all rats in both groups continued to have severe proteinuria and that most animals died between 8 to 12 months after disease induction, without renal impairment. EM findings in serial biopsies demonstrated that the growth of the subepithelial deposits as measured by surface area occurred between weeks 4 and 12. A positive correlation (r = 0.94) between the size of the deposits and the level of proteinuria was found. These studies demonstrate that the membrane attack complex of complement does not play a major role in AHN. The relationship of the size of the immune deposits to the level of proteinuria suggests that the growth of the immune deposits on itself initiate secondary mechanisms that damage the permselective characteristics of the glomerular membrane.

Animals↗
PubMed1989

The molecular architecture of human complement component C6.

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.

Amino Acid Sequence↗
PubMed2004

Two cDNAs from the purple sea urchin, Strongylocentrotus purpuratus, encoding mosaic proteins with domains found in factor H, factor I, and complement components C6 and C7.

The vertebrate complement system is composed of about 30 serum and cell surface proteins that make up three activation pathways, a lytic pathway, and a set of proteins that regulate complement. Regulatory proteins are required for host protection against autologous complement attack and to control the amplification feedback loop of the alternative pathway. Purple sea urchin, Strongylocentrotus purpuratus, homologues of complement C3 (SpC3) and factor B (SpBf) have been identified, suggesting the presence of an alternative complement pathway. This implies that echinoderms require a complement regulatory system for the same reasons that it is required in higher vertebrates. Two cDNAs, Sp5 and Sp5013, have been characterized from coelomocytes and the deduced structures of the encoded mosaic proteins, SpCRL ( S. p urpuratus complement related protein, long form) and SpCRS ( short form), have domains that are also found in regulatory proteins such as factor H and factor I and the terminal pathway components C6 and C7. These domains include multiple short consensus repeats, a fucolectin domain, Ser/Thr/Pro-rich regions, a Cys-rich region, and a factor I-membrane attack complex domain. The genes are constitutively expressed in all tissues of the sea urchin and are not induced in response to immune challenge. Multiple bands of varying intensity on both genome blots and RNA blots suggest that Sp5 and Sp5013 are members of a small gene family and that they might undergo alternative splicing. Based on the domains present in SpCRL and SpCRS, they might be either examples of complement regulatory proteins or members of the terminal pathway of complement.

Amino Acid Sequence↗
PubMed1985

Close linkage between mouse genes determining the two forms of complement component C6 and component C7, and cis action of a C6 regulatory gene.

Two forms of mouse complement component C6, with molecular weights (Mrs) of 90 and 100 kilodaltons (kd), are present in the sera from certain inbred strains such as the CBA strain; other strains, such as the BALB/c and DBA/2 strains, have only the 90 kd C6A form. The present work was undertaken to determine whether the two Mr forms were the products of genes coding at separate loci. We screened sera from mice from a number of inbred strains by isoelectric focusing and found one strain, AKR, exhibiting allotypic structural variations of C6 forms. To distinguish the various types, we designated the 90 kd types from CBA and AKR mice C6A1 and C6A2, respectively, and the corresponding 100 kd types C6B1 and C6B2, respectively. Mice possessing only one Mr form were all typed as C6A1. Results of breeding experiments strongly suggested that the two Mr forms of C6 are coded for at two closely linked loci. Sera from a number of inbred strains were also screened for a complement C7 polymorphism by means of isoelectric focusing and functional overlay. C7 from all strains, excepting the AKR strain, produced identical C7 band patterns. AKR C7 produced a unique band pattern, and results of breeding experiments with AKR and BALB/c mice showed the C6 and C7 loci to be closely linked. In addition, we identified a regulatory gene for C6 production. The gene apparently requires androgen to facilitate C6 production in the majority of strains. In these strains C6 activity is virtually absent from female sera. However, we observed moderate levels of C6 activity in sera from IS/Cam females, indicating that, in this strain, male physiological androgen levels are not necessary for C6 production. IS/Cam possess one form of circulating C6 which appears identical with BALB/c C6A1, and therefore IS/Cam mice differ from AKR mice at both the C6 structural and regulatory loci. These two strains were thus suitable for use in breeding experiments to determine the manner of action of the regulatory gene. Results showed that it acted in a cis manner.

Animals↗
PubMed1993

A physical map of the human complement component C6, C7, and C9 genes.

The genes for human complement components C6, C7, and C9 are linked on chromosome 5. In this report we describe the physical linkage between C6 and C7 genes. DNA fragments obtained by digestion with several rare-cutting restriction enzymes were separated through pulsed field gel electrophoresis. Hybridization with probes corresponding to the 5' and 3' ends of the three cDNAs showed common bands for the C6 and C7 genes. Both genes are contained in a NotI fragment of 500 kilobases (kb). Moreover, the presence of common 3' C6 and 3' C7 fragments indicates that both genes are oriented in a tail-to-tail, reverse way relative to transcription. No evidence of physical linkage between C9 and C6 or C7 was found in the range 50 kb-2.5 megabases (Mb).

Chromosome Mapping↗
PubMed2005

Nucleotide sequence analyses of human complement 6 (C6) gene suggest balancing selection.

The sixth complement component (C6) has a common charge polymorphism, C6A and C6B, with similar gene frequencies in all major populations. In addition, C6B2 is also found in Japanese populations at a frequency of about 6%. Sequence analyses of the coding region of three human and ape C6 alleles indicated four nonsynonymous and three synonymous changes in C6*B2 relative to C6*A, suggesting that a recombination event occurred between C6*B2 and C6*A to give rise to C6*B. Sequence variation in a 3.86 kb region encompassing exon 3, where the causal base change of the common C6 polymorphism is found, indicated that several single nucleotide polymorphisms (SNPs) were in extensive linkage disequilibrium (LD), with little differentiation among populations. Sliding window estimates of two test statistics for neutrality revealed significant values in a subregion where the replacement coding polymorphism resides, in all three human populations. These results raise the possibility that the two common C6 alleles in human populations are maintained by balancing selection.

Animals↗
PubMed1999

Function of the factor I modules (FIMS) of human complement component C6.

In order to elucidate the function of complement component C6, truncated C6 molecules were expressed recombinantly. These were either deleted of the factor I modules (FIMs) (C6des-748-913) or both complement control protein (CCP) modules and FIMs (C6des-611-913). C6des-748-913 exhibited approximately 60-70% of the hemolytic activity of full-length C6 when assayed for Alternative Pathway activity, but when measured for the Classical Pathway, C6des-748-914 was only 4-6% as effective as C6. The activity difference between C6 and C6des-748-913 for the two complement pathways can be explained by a greater stability of newly formed metastable C5b* when produced by the Alternative Pathway compared with that made by the Classical Pathway. The half-lives of metastable C5b* and the decay of (125)I-C5b measured from cells used to activate the Alternative Pathway were found to be about 5-12-fold longer than those same parameters derived from cells that had activated the Classical Pathway. (125)I-C5 binds reversibly to C6 in an ionic strength-dependent fashion, but (125)I-C5 binds only weakly to C6des-FIMs and not at all to C6des-CCP/FIMs. Therefore, although the FIMs are not required absolutely for C6 activity, these modules promote interaction of C6 with C5 enabling a more efficient bimolecular coupling ultimately leading to the formation of the C5b-6 complex.

Animals↗
PubMed1998

Molecular defects leading to human complement component C6 deficiency in an African-American family.

Complement component C6 deficiency (C6D) was diagnosed in a 16-year-old African-American male with meningococcal meningitis. The patient's father and two brothers also had C6D, but gave no history of meningitis or other neisserial infection. By using exon-specific polymerase chain reaction (PCR)/single-strand conformation polymorphism as a screening step and nucleotide sequencing of target exons, we determined that the proband was a compound heterozygote for two C6 gene mutations. The first, 1195delC located in exon 7, is a novel mutation, while the second, 1936delG in exon 12, has been described before to cause C6D in an unrelated African-American individual. Both mutations result in premature termination codons and C6 null alleles. Allele-specific PCR indicated that the proband's two brothers also inherited the 1195delC mutation from their heterozygous mother and the 1936delG mutation from their homozygous father.

Adolescent↗
PubMed1991

DNA polymorphisms and linkage relationship of the human complement component C6, C7, and C9 genes.

In this report we describe the linkage between genes encoding human complement components C6, C7, and C9. Polymorphisms have been described at the DNA level for the C7 and C9 genes. We have studied 20 individuals by Southern blot analysis with four C6 cDNA subclones to detect restriction fragment length polymorphisms (RFLPs). We have found a Taq I polymorphism defined by two alleles of 8.0 (C6 H) and 6.0 (C6 L) kilobases (kb). RFLP segregation for the C6, C7, and C9 loci in informative families allowed us to estimate the maximum Lod scores at a recombination fraction of theta = 0.0 (C6-C7), theta = 0.0 (C7-C9), and theta = 0.0 (C6-C9). Significant linkage disequilibrium was found between C6 and C7 and between C7 and C9 loci in directly determined haplotypes of unrelated parents. Data from this study show that the genes encoding the human terminal complement components C6, C7, and C9 define a cluster in the short arm of chromosome 5. We propose that the clusters involving the C8A and C8B and the C6, C7, and C9 genes be referred to as MACI and MACII, respectively.

Chromosome Mapping↗
PubMed1992

Properties of a low molecular weight complement component C6 found in human subjects with subtotal C6 deficiency.

A sensitive ELISA assay was used to quantitate serum complement component C6 concentrations. Levels in the range 0.3-3 micrograms/ml were measured in samples from eight individuals (four separate pedigrees) and two subjects with subtotal combined C6/C7 deficiency who have been reported previously. We defined C6 levels in this range as subtotal C6 deficiency (C6SD). In contrast, C6 deficiency with levels below 0.03 micrograms/ml was defined as C6Q0. C6Q0 has been found in 29 unrelated cases which have already been reported. Investigations of the properties of the C6 found in the C6SD subjects showed it to be haemolytically active and able to incorporate into the terminal complement complex. The protein had a relative molecular weight (Mr) of approximately 86% of normal C6 and this Mr was identical to that of the C6 of one combined deficient subject. The Mr of the C6 of the other combined deficient subject was previously estimated as 79% of the Mr of normal C6. Isoelectric focusing (IEF) analysis with band development by haemolytic overlay revealed that all C6SD samples produced an identical weak C6 band pattern anodal to normal C6A bands. The C7 IEF patterns of the two combined deficient subjects were identical, and the C6 IEF patterns of both were identical to those of the C6SD subjects. Thus the C6 of the combined deficient subjects is probably the same abnormal protein found in the C6SD individuals. None of the C6SD or combined deficient subjects have had meningococcal disease and it may be that low C6 levels afford some protection.

Adult↗
PubMed1992

Genetic polymorphism of complement component C6, C7 and C8(1) in Chinese Han population in northeast China.

Distributions of complement phenotypes, C6, C7, and C8(1) were studied using thin agarose gel isoelectric focusing (AGIEF) or ultra-thin polyacrylamide gel isoelectric focusing (PAGIEF) and subsequent immunoblotting techniques in 203 Chinese Han population in Liaoning Province of northeast China. The gene frequencies were as follows: C6*A 0.4704, C6*B 0.5049, C6*B2 0.0148, C6*B3 0.0049, and C6*M 0.0049; C7*1 0.8251, C7*2 0.1108, C7*3 0.0320, and C7*4 0.0320; C8(1)*A 0.5567 and C8(1)B 0.4433, respectively. All the observed numbers of the phenotypes were in agreement with the expected numbers under the Hardy-Weinberg equilibrium. The gene frequencies among Chinese subpopulations and other various populations were compared.

Asian People↗
PubMed1998

Reference typing report for complement components C6, C7 and C9 including mutations leading to deficiencies.

The results of the present (VIIth Complement Genetics Workshop and Conference, Mainz, May 1998) and past reference typing workshops for the terminal complement components C6, C7 and C9 are compiled and discussed both on the protein level and on the DNA level. This report also focuses on the molecular bases of expressed and silent polymorphisms and reviews the molecular bases of subtotal and complete deficiencies of these proteins and their associations with protein and DNA markers. The results of the protein typing for C6 are published in the following paper of this issue.

Alleles↗
PubMed1993

Polymorphism of human complement component C6: an amino acid substitution (Glu/Ala) within the second thrombospondin repeat differentiates between the two common allotypes C6 A and C6 B.

Component C6 of the human complement system exhibits a genetic polymorphism in all populations tested so far. Using isoelectric focusing two common allotypes, C6 A ('acidic') and C6 B ('basic') and a number of rare variants have been described. A comparison of the two published cDNA sequences of C6 suggests a polymorphism in codon 98. Using polymerase chain reaction (PCR) we amplified a segment of the human C6 gene encompassing the presumably polymorphic codon. According to the restriction fragment patterns obtained after DdeI digestion of the PCR product, three genotypes were distinguished. The polymorphism is caused by a nucleotide substitution (C-->A) in the second position of codon 98; allele 1 (GCG) codes for Ala, allele 2 (GAG) for Glu. Sequencing of PCR products confirmed the mutation. For 46 unrelated individuals genotyped by this PCR-based method we also determined C6 protein phenotype. Three phenotypes were observed (C6 A, C6 AB, C6 B). There was an absolute concordance between C6 protein typing and DNA typing. We thus conclude that the C6 A allotype is characterized by a Glu and the C6 B allotype by an Ala residue in position 98 of the C6 polypeptide chain.

Alanine↗
PubMed2000

High prevalence of complement component C6 deficiency among African-Americans in the south-eastern USA.

Complement component C6 is a part of the membrane attack complex that forms a pore-like structure in cell membranes following complement activation. Deficiency of terminal complement components including C6 predisposes individuals to infection with Neisseriae. Using polymerase chain reaction/single-strand conformation polymorphism analysis followed by DNA sequencing, we screened genomic DNA from 200 randomly chosen blacks and an equal number from whites for three loss-of-function C6 mutations. Ten blacks and two whites were found to be heterozygous for one of the mutations. Two of the mutations, 1195delC and 1936delG, were found exclusively in black individuals. A third previously undescribed mutation, 878delA, was found at equal frequency among the two groups. The difference between the two groups was significant (P = 0.027), indicating that C6 deficiency due to these three mutations is more common among blacks than whites in the local area, principally Jefferson County, Alabama. In addition, three previously undescribed point mutations, two of which result in amino acid substitutions, were identified within exon 6. A review of the county health department records over the past 6 years revealed a higher incidence of meningococcal meningitis in blacks due to serogroups Y and W-135 which paralleled the difference in the estimated prevalence of C6 deficiency. Among black residents of the county (n = 235 598) there were 15 cases of meningitis due to these two serogroups, compared with two cases in the white population (n = 422 604) (P = 0.002). We conclude that C6 deficiency is more common among blacks than whites in the south-eastern United States, with a frequency approaching 1 in 1600 black individuals.

Amino Acid Sequence↗