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At least 19 recordsLinked to original sources
PubMed1989

Complete primary structure and functional characterization of the sixth component of the human complement system. Identification of the C5b-binding domain in complement C6.

Complement C6 is one of five plasma proteins that are incorporated into the lytic terminal complement complex on lipid membranes (C5b-9m) upon activation of the complement cascade. Oligonucleotide probes derived from partial amino acid sequences of purified C6 were used to isolate cDNA clones from a human liver cDNA library. The complete polypeptide structure of mature C6 deduced from the cDNA sequence consists of 913 amino acid residues preceded by a typical 21-residue signal peptide. C6 is most similar in structure to complement C7, sharing 33.5% identical residues with C7 including all 56 cysteine residues. The low density lipoprotein receptor class A and B modules, the thrombospondin type I module at the carboxyl terminus, and the two short consensus repeat modules are arranged in the same way as in C7. In contrast to C7 and other terminal complement proteins, the thrombospondin type I module at the amino terminus occurs as a tandem repeat in C6. The last tandem repeat at the carboxyl terminus of C6 and C7 has been identified as a new distinct module (factor I module), which is closely related to a segment in the heavy chain of complement control factor I. Binding studies with filter-bound C6 fragments generated by proteolysis showed that the C5b-binding domain of C6 was located in the 34-kDa carboxyl terminal fragment consisting of two short consensus repeats and two factor I modules.

Amino Acid Sequence↗
PubMed2003

Restricted genetic defects underlie human complement C6 deficiency.

Complement C6 homozygous deficiency (C6D) has been rarely observed in Caucasians but was reported at higher prevalence among African-Americans. We report on the molecular basis of C6D in seven unrelated black individuals of North or Central Africa descent who live in France. These patients have presented Neisseria meningitidis infection (four cases), focal and segmental glomerulosclerosis with hyalinosis (one case), systemic lupus erythematosus (one case) or Still's disease (one case). All patients exhibited undetectable antigenic C6 by using a sensitive ELISA assay. An additional four cases of complete C6 deficiency with no associated disease have been characterized after family studies. Exons 6, 7 and 12 have been described recently as the location of molecular defects on the C6 gene in randomly chosen black Americans. Genomic DNA from the seven patients were subjected to direct polymerase chain reaction amplification of these three exons. Nucleotide sequencing analysis of the amplified DNA fragments revealed a homozygous single-base deletion (1936delG) in exon 12 in three cases and four compound heterozygous deletions for a single base in exon 7 (1195delC) or in exon 6 (878delA) associated with the same deletion in exon 12 (1936delG). Our observations further establish the restricted pattern of genetic defects associated with homozygous C6 complement deficiency in individuals of African descent.

Adolescent↗
PubMed1995

Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6.

Individuals with subtotal complement C6 deficiency possess a C6 molecule that is 14% shorter than normal C6 and present in low but detectable concentrations (1-2% of the normal mean). We now show that this dysmorphic C6 is bactericidally active and lacks an epitope that was mapped to the most carboxy-terminal part of C6 using C6 cDNA fragments expressed as fusion proteins in the pUEX expression system. We thus predicted that the abnormal C6 molecule might be carboxy-terminally truncated and sought a mutation in an area approximately 14% from the carboxy-terminal end of the coding sequence. By sequencing PCR-amplified products from this region, we found, in three individuals from two families, a mutation that might plausibly be responsible for the defect. All three have an abnormal 5' splice donor site of intron 15, which would probably prevent splicing. An in-frame stop codon is found 17 codons downstream from the intron boundary, which would lead to a truncated polypeptide 13.5% smaller than normal C6. This result was unexpected, as earlier studies mapped the C5b binding site, or a putative enzymatic region, to this part of C6. Interestingly, all three subjects were probably heterozygous for both subtotal C6 and complete C6 deficiency.

Amino Acid Sequence↗
PubMed1985

C3 and C6 complement types in schizophrenia.

C3 and C6 complement types were studied in schizophrenic patients and controls. The distributions of the three common C3 types (F, FS and S) among the patients was significantly different from that in the controls (p less than 0.005) and the frequency of the C3F gene was significantly increased (p less than 0.0005) among the patients. There were no significant differences in C6 gene or phenotype frequencies between patient and controls.

Complement C3↗
PubMed1997

Characterization of complement C6 deficiency in a PVG/c rat strain.

Complement C6 plays an important role in the effector phase of complement-mediated cell lysis. Recently, a PVG/c rat strain deficient in haemolytic C6 activity was discovered. In the present study we show that these rats lack both antigenic and functional C6, and that repetitive immunization of these rats with PVG/c+ serum results in generation of specific anti-rat C6 antibodies. The observed absence of rat C6 was further investigated at the genomic and transcriptional level using a 492-bp cDNA of rat C6, cloned from a rat liver cDNA library using full length human C6 as a probe. Northern blot analysis revealed the presence of C6 mRNA in livers of both PVG/c- and PVG/c+ rats, corresponding to a size of approximately 3.3 kb, although the level of C6 mRNA expression was approximately 100-fold less in PVG/c- rats. In addition, using rat C6-specific primers, positive signals were obtained in kidneys of both rat strains by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Southern blot analysis of digested genomic DNA did not reveal evidence for large C6 gene deletions. We conclude that the lack of C6 protein in the PVG/c- rat strain is not due to a (large) C6 gene deletion, but presumably is caused by an unstable mRNA or a point mutation in the C6 gene resulting in an aberrant transcription of the C6 gene. Alternatively, a gene coding for a product involved in C6 biosynthesis that acts in trans may carry a mutation.

Animals↗
PubMed1997

An unusual combined insertion/deletion polymorphism in intron 10 of the human complement C6 gene.

Investigation of intron 10 of the human complement C6 gene revealed an unusual combined insertion/deletion polymorphism at position 493: the subsequent 6 bp is deleted and is substituted by a different 26 bp, giving a net gain of 20 bp. The variant shows autosomal co-dominant inheritance. The 26 bp insertion is homologous to a human endogenous retrovirus-type sequence and could tentatively be ascribed to a retroposon. Alternatively, the presence of three copies of a 5 bp direct repeat, an 8 bp palindrome and a 12 bp split symmetrical element could suggest an endogenous, sequence-mediated mutational process. Polymorphisms of this type are extremely rare, although there are several examples of such mutations causing disease.

Base Sequence↗
PubMed1980

Polymorphism of the sixth component of complement (C6) in Norwegian Lapps.

Typing of the sixth component of complement (C6) was performed on serum samples from 167 unrelated Norwegian Lapps. The following allele frequencies were found: C6A, 0.53 and C6B, 0.47. The phenotype distribution was in good agreement with Hardy-Weinberg expectations. Variant phenotypes were not observed. A preliminary material of 1,623 non-Lappish Norwegians showed the following allele frequencies: C6A, 0.59 and C6B, 0.41. The difference in allele distribution between the two materials was statistically significant.

Adult↗
PubMed1993

Genetic polymorphism of the sixth component of complement (C6) in the pig.

Using agarose gel isoelectric focusing and immunoblotting with rabbit anti-rabbit C6, a genetic polymorphism has been found in the sixth component of complement (C6) in six breeds of pigs. The C6 locus was highly polymorphic. Family data indicated that pig C6 phenotypes were inherited by means of five codomonant alleles named C6A, C6B, C6C, C6D and C6E at a single autosomal locus. C6 deficiency in two of 241 individuals tested was found, which suggested the presence of a null allele in pig populations. Marked breed differences among the gene frequencies and heterozygosities at C6 locus were observed.

Animals↗
PubMed1995

Genetic polymorphism of the sixth component of complement (C6) in dogs.

Using agarose gel isoelectric focusing and immunoblotting with rabbit anti-rabbit C6, a genetic polymorphism was found in the sixth component of complement (C6) in 18 Asian native breeds or populations and three European breeds of dog. The C6 locus was highly polymorphic. The phenotype distribution data indicated that dog C6 phenotypes were controlled by seven codominant alleles, C6A,C6B,C6C,C6D,C6E,C6F and C6G, at a single autosomal locus. Breed differences were observed among the gene frequencies, especially between Asian and European breeds. Two gene flows from the adjacent areas into Japanese native dogs were postulated.

Animals↗
PubMed1977

Genetic polymorphism of the sixth component of complement (C6) in the rhesus monkey.

With isoelectric focusing, the complement protein C6 has been shown to be genetically polymorphic in the rhesus monkey. Three codominant alleles of a single autosomal locus, Rh C6, have been recognized: C6A, C6B, and C6R, with gene frequencies of 0.592, 0.354, and 0.053 in a random rhesus monkey population. Hardy-Weinberg analysis of the phenotypic frequencies in this population yielded observed values very close to those expected. Both natural mating between individuals carrying the various alleles and artificial combinations of sera of the different C6 types demonstrate patterns consistent with this model. Analysis of several families of monkeys confirmed the Mendelian autosomal codominant inheritance with numbers of offspring very close to expected values and no offspring types inconsistent with the mating pair types.

Animals↗
PubMed1971

A blood coagulation abnormality in rabbits deficient in the sixth component of complement (C6) and its correction by purified C6.

Evidence for the involvement of the sixth component of complement (C6) in normal blood coagulation is provided by the description of a coagulation abnormality in rabbits with a genetic C6 deficiency and by its correction with highly purified preparations of C6. Whole blood clotting time in glass or plastic was prolonged and prothrombin consumption was decreased in blood from the deficient animals. Other parameters of blood coagulation were normal, including prothrombin time, partial thromboplastin time, specific clotting factor activities, platelet factor III function, platelet count, and bleeding time. Clotting time and prothrombin consumption became normal when physiologic amounts of highly purified C6 were added to the deficient blood. Partial consumption of C6 hemolytic activity, with a time course similar to the consumption of prothrombin, was demonstrated during the clotting of normal human blood.

Animals↗
PubMed1995

Genetic detection of the silent allele (*Q0) in hereditary deficiencies of the human complement C6, C7, and C9 components.

DNA polymorphisms (RFLPs) of the human complement component C6, C7, and C9 genes were studied in three C7-deficient (C7D) families, one C6-deficient (C6D) family, and one C9-deficient (C9D) family. The 3 loci are closely linked on human chromosome 5. The haplotypes carrying the "silent" allele (C7*Q0, C6*Q0, and C9*Q0) were defined in each family, allowing for the detection of carriers among asymptomatic relatives. This paper describes familial studies on a type of hereditary trait, characterized by recurrent Neisseria infections in individuals homozygous for "silent" alleles at the C6, C7, or C9 loci.

Alleles↗
PubMed1983

Polymorphism of the sixth component of complement (C6) in the dog.

Isoelectric focusing was used to identify five alleles at the locus determining the production of the sixth component of complement (C6) in the dog. Four of these alleles, C6(1), C6(2), C6(4), and C6(5), were studied in family pedigrees and shown to be inherited in a codominant autosomal fashion. All alleles except for C6(4) occurred commonly in the multiple breeds tested.

Alleles↗
PubMed1988

Biochemical characterization of the human complement protein C6. Association with alpha-thrombin-like enzyme and absence of serine protease activity in cytolytically active C6.

Complement protein C6 has been proposed by others to be a serine protease whose activity is obligatory for complement-directed cell lysis. We separated the serine protease (Mr approximately 30,000) activity found associated with apparently homogeneous preparations of C6 from the hemolytically active C6 protein. The protease was characterized as thrombin-like based on substrate specificity, inhibitor profile, and kinetic studies. Although the proteolytic activity of C6 preparations was inhibitable by several inhibitors of serine proteases, the C6 hemolytic activity remained unaffected. Acid-induced (C(5,6)a complex formation between C5 and C6 (protease-free) was demonstrated by ion-exchange fast protein liquid chromatography, reversed-phase high performance liquid chromatography, and reactive cytolytic activity in the presence of C7, C8, and C9; but no cleavage of the alpha-chain of C5 was observed. Diisopropylphosphorofluoridate pretreatment of the components did not affect their ability to generate functionally active (C(5,6)a. Evidently, C6-associated thrombin is not required for formation of functional C(5,6)a. Thus, C6 does not function in the membrane attack pathway of complement as a serine protease. A method for the isolation of homogeneous C6 in the hemolytically fully active form is described. No free sulfhydryl group was detected in C6. The amino acid sequence of 20 amino-terminal residues was determined.

Amino Acid Sequence↗
PubMed1989

Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6.

The role of the lytic complement C5b-9 membrane attack complex (MAC) in acute passive transfer experimental autoimmune myasthenia gravis (EAMG) produced in rats was investigated by in vivo inhibition of MAC formation with anti-C6 Fab. Anti-C6 Fab totally inhibited in vitro serum hemolytic activity, but did not consume or inhibit early complement pathways. Injection of rats with 0.12 mg/ml anti-C6 Fab reduced serum C6 to 8% and inhibited the muscle weakness, electrophysiologic abnormalities and loss of acetylcholine receptor (AChR) associated with acute EAMG. This level of C6 inhibition reduced the total serum complement hemolytic activity to 29% of normal but did not reduce the serum levels of complement components C3, C5, or C7. Treatment of rats with lower amounts of anti-C6 Fab (0.08 mg/ml) also inhibited clinical and electrophysiologic signs of EAMG, however, the lower amount of anti-C6 did not prevent the loss of muscle AChR. Both the higher and the lower amount of anti-C6 Fab inhibited the accumulation of macrophages at muscle motor end-plates. The inhibition by anti-C6 indicates that muscle weakness and electrophysiologic abnormalities associated with EAMG are dependent on the complement MAC, and that muscle weakness results from tissue injury in addition to loss of muscle membrane and AChR.

Animals↗
PubMed1984

Genetic polymorphism of complement C6 and haplotype analysis between C6 and C7 in a Japanese 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.

Complement C6↗
PubMed1982

Genetic variation of the sixth component of complement (C6) in the Manx shearwater (Puffinus p. puffinus).

A polymorphism in the sixth complement component (C6) has been investigated by isoelectric focusing. The results indicate that C6 is coded by genes at a single autosomal locus. Six structural alleles have been identified, a null allele is also postulated. Five island colonies of Shearwater were investigated, two alleles C6 A and C6 B predominate in all sites. The ability of rabbit C5 and C7 to combine successfully with avian C6 indicates the functional sites of these molecules are highly conserved.

Animals↗