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PubMed1990

The assignment of the genes coding for human complement components C6 and C7 to chromosome 5.

A panel of 19 somatic cell hybrids was tested for the presence of human sequences coding for complement components C6 and C7 by restriction enzyme digestion and Southern blots probed with human C6 and C7 cDNA probes. C7 was also detected by amplifying part of the human gene in hybrid DNA using the polymerase chain reaction. Detection of human C6 and C7 was completely correlated with the presence of chromosome 5.

Animals↗
PubMed1984

Genetic polymorphism and linkage of the sixth and seventh complement components (C6 and C7) in the common marmoset.

Using polyacrylamide gel isoelectric focusing and standard specific hemolytic detection methods, genetic polymorphisms have been found in the sixth and seventh complement components (C6 and C7) in two laboratory groups of Common marmosets. The C6 locus is highly variable and the products of six alleles were observed; three C7 alleles were found. Comprehensive breeding data indicated that both sets of alleles are inherited in an autosomal codominant manner. Many of the C6 variants differed only by a minute charge interval. The C7 variant bands differed by large charge intervals and could only be clearly seen in plasmas that had been preincubated with neuraminidase. A linkage analysis of C6 and C7 phenotypes in three, two-generation families gives reasonable evidence that the two loci are linked in marmosets as they are in humans.

Alleles↗
PubMed1998

Reference typing report for complement component C6: protein typing.

Within the C6/C7/C9 Session of the VIIth Complement Genetics Workshop and Conference, various C6 protein allotypes collected from four laboratories were examined using polyacrylamide gel isoelectric focusing (PAGIF) followed by direct immunofixation. Nineteen different variants including 17 recognized allotypes and introducing two new allotypes were distinguished besides the two common allotypes C6 A and C6 B. They were designated basically according to the previous statement on C6 nomenclature. Details on C6 DNA markers and associations of C6 markers with deficiencies of terminal complement components are published in the preceding paper of this issue.

Complement C6↗
PubMed1979

Isolation of late complement components by affinity chromatography. II. Purification of the human complement component C6.

We developed a new procedure for the rapid and gentle isolation of the human complement component C6 comparable to that described previously for C9. The procedure is based on affinity chromatography. As a first step, C6 is immunoabsorbed on insolubilized anti-C6 antibodies. These antibodies were derived from C6-defective rabbits (Freiburg strain). C6 was eluted with 3 M thiocyanate, pH 7.2, with a recovery of 15--23% of its hemolytic activity and a more than 270--fold purification. Impurities were removed in a second step by an "anti-impurity" column. The final product yielded a 12% recovery of the hemolytic activity and the purification factor was higher than 1300. The final product was homogeneous in SDS polyacrylamide and immunoelectrophoresis.

Animals↗
PubMed1999

No evidence for association of multiple sclerosis with the complement factors C6 and C7.

Four genome screens in multiple sclerosis have been completed and each has identified evidence for linkage in the pericentromeric region of chromosome 5. This region encodes a number of candidate genes including those for the complement components C6, C7 and C9. We have used a multiplexed oligoligation assay (OLA) to test single nucleotide polymorphisms (SNPs) from the C6 and C7 genes for evidence of association with multiple sclerosis in our sibling pair families. There was no statistically significant difference in the allele frequencies of these polymorphisms in the index cases from our families when compared with locally derived controls. No evidence for transmission distortion was seen with any of the polymorphisms, or with the haplotype built from the three SNPs from the C7 gene. Despite offering themselves as potential candidates these complement genes appear not to confer susceptibility to multiple sclerosis.

Autoimmune Diseases↗
PubMed1995

Complement component C6 and C7 haplotypes associated with deficiencies of C6.

Both complete C6-deficiency (C6*Q0) and subtotal C6-deficiency (C6*SD) have been described as simple recessive traits and C6*SD has been described in combination with subtotal deficiency of the C7 coded at an adjacent locus. The trace of C6 protein found in both C6*SD traits is phenotypically indistinguishable, being smaller than normal C6 and having different isoelectric properties. A defect has been found in the C6 gene which plausibly explains the C6*SD phenotype, and this defect is also common to both C6*SD traits. We present data from seven DNA markers of the C6 and C7 genes which show that although at least four haplotypes are associated with C6*Q0, most South African C6*Q0 patients carry a common defective haplotype. The most common haplotype associated with C6*Q0 has been observed only once among unaffected haplotypes of relatives. In one family, the cases of C6*SD share a complete haplotype with both cases of combined deficiency and are probably heterozygous for this condition and complete deficiency of C6. In another family, the C6*SD is on a slightly different haplotype and C7 is normally expressed. Thus, the C6 defect is not sufficient on its own to explain the C7 deficiency in the combined deficient haplotype. The haplotype associated with the combined deficiency is found not only in normal control subjects, but also in one case of complete C6 deficiency. In this case the molecular defect seen in combined or C6*SD cases is absent.

Alleles↗
PubMed1989

A case of hereditary combined deficiency of complement components C6 and C7 in man.

Immunological investigation of a patient presenting with candidiasis and toxoplasmosis revealed a combined deficiency of C6 and C7. Deficiency of C6 was total, but small amounts (less than 1 microgram/ml) of apparently normal C7 were present in the serum. All family members (three sibs and both parents) were heterozygous for the combined deficiency. This is only the second reported case of combined homozygous deficiency of the closely linked and immunochemically similar proteins C6 and C7, and only the third kindred in which this defect has been demonstrated.

Adult↗
PubMed1980

Familial late complement component (C6, C7) deficiency with chronic meningococcemia.

Two patients with chronic meningococcemia were found to lack hemolytic complement, one because of C6 deficiency, the other because of C7 deficiency. In both cases family studies were consistent with inheritance of the deficiencies as non-HLA-linked, autosomal co-dominant traits. Functional studies showed the deficient sera to support monocyte chemotaxis but not phagocytosis or lysis of meningococci. Both patients have remained well following antibiotic treatment.

Adolescent↗
PubMed1992

C7 M/N protein polymorphism typing applied to inherited deficiencies of human complement proteins C6 and C7.

C7 M/N typing, the determination of the complement component C7 M/N phenotypes, was successfully used in family studies to trace haplotypes bearing C7 deficiency genes. Furthermore, it was shown to be preferable to C7 allotyping based on isoelectric focusing (IEF) since it distinguishes two common alleles (C7*M and C7*N), whereas one common C7 IEF allele (C7*1) predominates in most populations. It is also the more sensitive method, as it enabled detection of very low amounts of abnormal C7 molecules in the third generation of a combined subtotal C6/C7-deficient subject and thus confirmed that this partial deficiency gene is not silent in heterozygotes. In this respect C7 M/N typing is even more informative than DNA restriction fragment length polymorphism typing which will assess the presence but not necessarily the functional status of a gene. C6 and C7 genes are tightly linked and therefore C7 M/N typing was also applied to tracing C6 deficiency genes in families. C6/C7 haplotype analysis of South African C6-deficient (C6Q0) subjects revealed a strong allelic association of C6*Q0 and C7*M.

Alleles↗
PubMed1988

Allotypes of mouse complement component C6 in inbred strains and some wild populations.

This collaborative work was undertaken to resolve discrepancies in reports of the number of forms of complement component C6 present in the circulation of mice from various inbred strains. Plasma C6 was analyzed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and by isoelectric focusing (IEF), and C6 band patterns were developed by electroblotting and immunoprobing. Results of C6 allotyping of mice from 36 strains confirmed that while 20 strains (prototype strain BALB/c) possessed only one relative mass (Mr) for which typed C6A1 on IEF, the other 16 strains all possessed more than one C6 Mr form. Moreover, IEF analysis demonstrated additional polymorphic differences; among these 16 strains, 11 typed C6A1B1 like the prototype strain CBA, the AKR and RF/J strains typed C6A2B2, and the Japanese MOM strain as well as the C57BR/cdJ and C57L/J strains possessed two forms with IEF mobilities intermediate between C6A1B1 and C6A2B2. These will now be referred to as C6A3B3. Thus, a total of four different mouse C6 haplotypes have been identified. Testing C6 allotypes in a limited number of wild mice revealed that haplotypes found in inbred strains of Western or Eastern origin tend to reflect haplotypes of the wild mice from Europe or Japan, respectively.

Animals↗
PubMed1991

Functionally active complement proteins C6 and C7 detected in C6- and C7-deficient individuals.

Two sensitive sandwich ELISAs based on monoclonal antibodies directed to native C6 and C7 allowed the detection and quantitation of these complement proteins in 20 out of 37 serum samples from individuals who had previously been classified as deficient in these proteins as assessed by immunochemical and/or functional assays. Furthermore, serum from four C6-deficient and one combined C6-/C7-deficient individual showed an increase in the terminal complement complex (TCC) and a decrease in native C6 and C7 after complement activation as assayed by specific ELISAs. Despite their (incomplete) deficiencies, these individuals therefore possess functionally active terminal complement proteins with respect to their ability to generate the TCC. As these individuals have no history of a susceptibility to neisserial infections, even low concentrations of functionally active C6 and C7 may provide sufficient protection against those micro-organisms whose destruction requires TCC formation.

Antibodies, Monoclonal↗
PubMed1984

Genetic polymorphism of the sixth component (C6) of rat complement.

The complement protein C6 has been shown to be genetically polymorphic in the rat. Isoelectric focusing of plasma samples from 19 inbred strains demonstrated two electrophoretically distinguishable migration patterns, each consisting of three bands. Breeding studies with the use of the BN and DA strains showed that the C6 patterns were inherited in a manner consistent with the co-dominant autosomal expression of two alleles (C6 A and C6 B). The distribution of the C6 alleles in a backcross mating was compared with eight independently segregating marker genes: RT1.A, RT2, Gdc -1, Igk-1, Hbb, Svp-1, Fh-1, and Es-6. There was no detectable linkage between C6 and any of these eight loci.

Animals↗
PubMed1998

Prolonged discordant xenograft survival by inhibition of the intrinsic coagulation pathway in complement C6-deficient recipients.

BACKGROUND: Xenotransplantation of vascularized organs between unmodified discordant species results in hyperacute graft rejection within minutes to hours after graft reperfusion. This process is due to the presence of natural xenoreactive antibodies and complement activation, which lead to vessel injury, thrombosis, and hemorrhage. Because multiple components of the coagulation and complement cascades interact with each other, we have investigated the effects of inhibiting these systems together. The recombinant Kunitz type serine protease inhibitor (KPI-BG022) tested in these experiments inhibits factor XIIa, kallikrein, and plasmin. METHODS: Cardiac xenografts from male Hartley guinea pigs were heterotopically grafted into male PVG rats that were either sufficient (C6[+]) or deficient (C6[-]) for the complement component C6 and thus formation of the membrane attack complex. Experimental animals received KPI 5 mg/kg intravenously before reperfusion, and control animals received saline placebo. RESULTS: C6(+) recipients rejected their grafts hyperacutely, without a significant difference between KPI-treated (0.12+/-0.05 hours) and placebo-treated (0.13+/-0.06 hours) recipients (n = 10). As expected, C6(-) recipients showed prolonged graft survival (17.65+/-3.45 hours, n = 5). However, a single intravenous bolus of KPI before releasing the clamps further delayed graft rejection in C6(-) recipients (46.2+/-3.3 hours; n = 5). Histologic examination at 2, 6, and 12 hours after transplantation showed platelet aggregation and inflammatory infiltrates were significantly decreased in KPI-treated (C6[-]) recipients. However, intragraft hemorrhage was apparent at 6 and 12 hours. CONCLUSIONS: We conclude that in vivo inhibition of the intrinsic clotting cascade by functional inactivation of factor XIIa has a synergistic effect with inhibition of membrane attack complex formation in preventing hyperacute discordant xenograft rejection.

Animals↗
PubMed1997

Elucidation of the disulfide-bonding pattern in the factor I modules of the sixth component (C6) of human complement.

Complement component C6 is known to contain two factor I modules in tandem at its C-terminus. To localize the disulfide bridges in those domains, native C6 was cleaved with trypsin, followed by subtilisin. The resulting digests were separated by reversed-phase HPLC, and all of the potential cystine-containing fragments were detected by a fluorescence assay and amino acid composition analyses. Final identification of the disulfide bonds was achieved by Edman degradation of the corresponding peptides. From the data gained a 1-3, 2-9, 4-7, 5-10, 6-8 pattern was determined (Cys752-Cys802, Cys763-Cys780, Cys765-Cys816, Cys772-Cys795, Cys841-Cys852, Cys846-Cys898, Cys859-Cys876, Cys861-Cys911, Cys867-Cys891). These findings are compared with the strongly related complement components C7 and factor I.

Amino Acid Sequence↗
PubMed1992

Complement genetic markers in schizophrenia: C3, BF and C6 polymorphisms.

Polymorphic variants of C3, BF and C6 complement factors have been investigated in schizophrenic patients subdivided according to the existence or not of a family history of both schizophrenia and other psychiatric disorders. To analyze the contingency tables, besides the usual methods, log-linear models have been fitted. Significant associations have been found in the C3 system, with a decrease of C3*F in patients (contradicting previous findings), and in the BF system, with a decrease of FS phenotype among patients (confirming some previous results). No association has been found for the C6 polymorphism (in accordance to previous results). Therefore, the present findings only partially confirm previous results and do not clarify the relationship between complement genetic markers and schizophrenia, stressing some statistical difficulties.

Alleles↗
PubMed1996

Molecular bases for inherited human complement component C6 deficiency in two unrelated individuals.

Deficiency of the sixth component of complement (C6D) is frequently associated with recurrent neisserial infections, especially meningitis caused by Neisseria meningitidis. We here report the molecular bases of C6D in two unrelated subjects, one African American (case 1) and the other Japanese (case 2). Screening all 17 exons of the C6 gene and their boundaries by exon-specific PCR/single strand conformation polymorphism demonstrated aberrant single stranded DNA fragments in exon 12 of case 1 and exon 2 of case 2. Nucleotide sequencing of the amplified DNA fragments revealed a homozygous single-base deletion (G1936) in exon 12 case 1 and a heterozygous single base deletion (C291/C292/C293/C294) in exon 2 of case 2. Both mutations resulted in frame shifts and premature termination of the C6 polypeptide. Sequence-specific oligonucleotide probe hybridization and direct sequencing of exon 12 amplified from genomic DNA further supported the homozygosity of the mutation in case 1. Case 2 is apparently compound heterozygote, but the putative mutation in the other allele of the C6 gene remains unknown. Both case 1 and case 2 were homozygous for the C6A allotype. These data indicate that at least three distinct mutational events can cause C6D, single nucleotide deletions in exons 2 and 12, and a mutation yet unidentified. Thus, similar to other complement protein deficiencies, the pathogenesis of C6D appears to be heterogeneous.

Adult↗