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PubMed1998

Molecular heterogeneity of second and fourth components of complement and their genes in systemic sclerosis and association of HLA alleles A1, B8 and DR3 with limited and DR5 with diffuse systemic sclerosis.

Deficiency of the complement component C4 at the functional, protein and gene level and deficiency of complement component C2 at the functional level were investigated and HLA analysis was performed on patients with limited and diffuse systemic sclerosis (SSc). One of the patients with limited SSc (n = 15) had subnormal C4, 1 subnormal C2 and 1 subnormal C4 and C2 activities; the latter patient had HLA alleles A11;B35;Dw1 associated with type II C2 deficiency and therefore most likely had a defect at the C2 locus. One of the patients with diffuse SSC (n = 12) had subnormal C4 and 1 subnormal C4 and C2 activities. C2 deficiencies in patients other than the one with the haplotype associated with C2 deficiency appeared not to be determined by the gene at the C2 locus. The incidence of partial C2 deficiency in a normal Caucasian population is reported to be 16 in 10,000, and that of partial C4 deficiency also appears to be very low. The percentages of C4A*Q0 and C4B*Q0 alleles in normal controls (n = 45) were within the reported range. Seven patients with limited SSc (n = 14) had one or two C4A*Q0 alleles and 2 with diffuse SSc (n = 13) had one C4A*Q0 allele. Thus, the incidence of C4A*Q0 was higher than normal in limited SSc and within the normal range in diffuse SSc. The two-sided Fisher's exact test applied on these data revealed that the association of C4A*Q0 with limited SSc did not reach a significant level (p = 0.10). Two of the 3 patients with limited SSc, who had two C4A*Q0 alleles, carried a heterozygous C4A-21-hydroxylase A (OHA) gene segment deletion as detected by Southern blotting. There was no correlation between the subnormal activity of C4 and the occurrence of one or two C4A*Q0 (and C4A-21-OHA segment deletion). HLA alleles A1, B8 and DR3 (p = 0.002) were associated with limited SSc (n = 23) and DR5(w11) (p = 0.018) with diffuse SSc (n = 17).

Alleles↗

PubMed2002

X-ray crystal structure of the C4d fragment of human complement component C4.

C4 fulfills a vital role in the propagation of the classical and lectin pathways of the complement system. Although there are no reports to date of a C4 functional activity that is mediated solely by the C4d region, evidence clearly points to it having a vital role in a number of the properties of native C4 and its major activation fragment, C4b. Contained within the C4d region are the thioester-forming residues, the four isotype-specific residues controlling the C4A/C4B transacylation preferences, a binding site for nascent C3b important in assembling the classical pathway C5 convertase and determinants for the Chido/Rodgers (Ch/Rg) blood group antigens. In view of its functional importance, we undertook to determine the three-dimensional structure of C4d by X-ray crystallography. Here we report the 2.3A resolution structure of C4Ad, the C4d fragment derived from the human C4A isotype. Although the approximately 30% sequence identity between C4Ad and the corresponding fragment of C3 might be expected to establish a general fold similarity between the two molecules, C4Ad in fact displays a fold that is essentially superimposable on the structure of C3d. By contrast, the electrostatic characteristics of the various faces of the C4Ad molecule show marked differences from the corresponding faces of C3d, likely reflecting the differences in function between C3 and C4. Residues previously predicted to form the major Ch/Rg epitopes were proximately located and accessible on the concave surface of C4Ad. In addition to providing further insights on the current models for the covalent binding reaction, the C4Ad structure allows one to rationalize why C4d is not a ligand for complement receptor 2. Finally the structure allows for the visualization of the face of the molecule containing the binding site for C3b utilized in the assembly of classical pathway C5 convertase.

Amino Acid Sequence↗

PubMed1990

CYP21B gene conversion and complete CYP21A gene deletion in congenital adrenal hyperplasia.

We studied a family in which one out of two children presented a non-salt wasting form of CAH. Genomic DNA of the patient, his brother, his parents and a normal control were digested by the Taq I and Bgl II restriction enzymes. The fragments were electrophoresed, transferred onto a nitrocellulose membrane and hybridized with two specific probes: pC21a for the CYP21 genes and pAT-A for the C4 genes. We performed simultaneous RFLP analyses of the CYP21 and C4 genes and determined the relative hybridization intensity of the genes using scanning densitometry of the X-ray films. The affected child had a CYP21B gene conversion in the CYP21A pseudogene on one chromosome inherited from his mother and a mutated CYP21B gene on the second chromosome inherited from his father. The second maternal chromosome, inherited by the unaffected brother, presented an unusual CYP21A gene deletion without a C4A or C4B gene deletion. Although CYP21A is a pseudogene, this type of complete CYP21A gene deletion associated with a CYP21B gene conversion has never been previously described.

Adrenal Hyperplasia, Congenital↗

PubMed1997

The mouse anaphylatoxin C3a receptor: molecular cloning, genomic organization, and functional expression.

The anaphylatoxin C3a receptor (C3aR) is unique among the family of G protein-coupled receptors in possessing an unusually large predicted second extracellular loop. To isolate the mouse C3aR, a probe derived from this extracellular loop was used to screen a mouse brain cDNA library. A 3.3-kb cDNA encoding an open reading frame of 477 amino acids was identified. The predicted amino acid contained four predicted N-linked glycosylation sites and was 65% identical to the 482 amino acids comprising the coding region of the human C3aR. Northern blot analysis revealed that this gene was expressed in a variety of mouse tissue and was especially abundant in heart and lung tissues. The mouse C3aR cDNA was used as a probe to isolate a mouse C3aR genomic clone. The nucleotide sequence of the mouse C3aR genomic clone was identical to the cDNA throughout the coding region, indicating that the receptor is encoded on a single exon. The C3aR cDNA was subcloned into a mammalian expression vector and transiently expressed in HEK-293 cells. Binding of radiolabeled C3a to the transfected cells was competed in a dose-dependent manner by increasing concentrations of unlabeled C3a, with a 50% inhibiting concentration of 10 nM. Similar to the human C3aR, RBL-2H3 rat basophilic cells stably expressing this receptor responded in a dose-dependent manner to C3a, a synthetic C3a peptide agonist, but not C4a or C5a, with a vigorous calcium mobilization.

Amino Acid Sequence↗

PubMed1985

Adrenal 21-hydroxylase cytochrome P-450 genes within the MHC class III region.

Genes encoding several serum complement components and the gene(s) for steroid 21-hydroxylase (21-OH) have been located in the class III region of the major histocompatibility complex (MHC). All these genes are highly polymorphic in man, and these polymorphisms have been used to draw conclusions about the structure and function of these genes. For example, electrophoretic polymorphisms of the fourth component of complement (C4) have been shown to be controlled by two closely linked genes, which also control expression of the red cell antigens Rodgers and Chido. Steroid 21-OH deficiency (D) can occur in several forms which differ in severity, and because of genetic linkage disequilibrium with different HLA antigens the inheritance of these forms is consistent with the existence of several alleles at a single locus. When severe 21-OH D occurs in association with the HLA haplotype A3;Bw47;DR7, there is a simultaneous null allele at one of the C4 loci. This was hypothesized to result from a single deletion or rearrangement affecting the 21-OH and C4 loci and perhaps the HLA-B gene as well. To test this hypothesis and identify the 21-OH gene, a cDNA clone was isolated which encoded the cytochrome P450 specific for steroid 21-hydroxylation in the bovine adrenal gland. This clone hybridized to two genes in normal human DNA, but to only one gene in DNA from an individual homozygous for A3;Bw47;DR7. All individuals heterozygous for A3;Bw47;DR7 carry a heterozygous deletion of a gene. These experiments showed that at least one structural gene for the cytochrome P450 specific for 21-hydroxylation is located in the MHC, probably very near the C4 genes, and a mutation in this gene results in 21-OH D. Cosmid clones have been used to locate the 21-OH genes both in man and mouse. In both species, there are two 21-OH genes, each located immediately 3' of one of the two C4 genes, and oriented in the same direction as the C4 genes. In man, the gene located 3' of the C4B gene is deleted in 21-OH D on the Bw47 haplotype, but the gene 3' of the C4A gene is deleted in hormonally normal individuals on the A1;B8;C4AQO;C4B1;DR3 haplotype. Thus the 21-OH B gene is normally active in man, but the 21-OH A gene is not.

Adrenal Glands↗

PubMed1989

Human BF*F-subtypes: segregation analysis with inclusion of MHC haplotypes.

The segregation of factor B(BF)F subtypes was analyzed in conjunction with other MHC markers in 15 families with 89 offspring. Informative data for BF F subtypes were obtained from 11 families, 6 of them with known recombinant individuals for the HLA-B/DR/GLO region. The subtypes did not contribute further to the localization of the cross-overs, but followed the known segregation of conventional BF allotypes. In 2 families of one kinship, the recognition of heterozygous BF*FAFB individuals could be established following the inclusion of three generations. The rarer of the two BF F subtype alleles, BF*FA, is positively associated with the HLA haplotypes BW62, CW3, C4A*3 and A29, CWX, B44, C4A*3, B*1, DR7. BF F subtypes are regarded as a very useful additional tool for studies of MHC organization and disease association.

Alleles↗

PubMed1987

C4 isotype deficiency in IgA nephropathy.

C4 and factor B typing were performed in 37 pediatric patients with primary IgA nephropathy. Null alleles for C4B occurred with a frequency of 26% in patients, as compared to 15% in healthy controls (NS). The phenotype of C4B deficiency (homozygous C4B null), however, was found in 16% of patients and 4% of controls (P less than 0.05). Comparison of observed C4B phenotypes with those predicted from the Hardy-Weinberg equilibrium also confirmed an excess of C4B deficiency (P less than 0.0005). In contrast, there was no evidence of distortion in the frequencies of the C4A null allele or phenotype, or of the factor B alleles. The data suggest that C4B deficiency may be one of multiple interacting factors contributing to the development of this glomerulopathy.

Adolescent↗

PubMed1982

The BF locus and HLA: rare alleles coding for functionally active and inactive factor-B products.

The genetic polymorphism of properdin factor B (BF) was studied in different populations. The rarer alleles, BF*F1 and BF*S1, occurred in Caucasians, were less frequent in North American blacks, and were not demonstrated in any of three Oriental populations studied. Two further alleles of BF, termed BF*FM and BF*SM, were found to exist in these populations. The BF*FM allele, which was found only in Caucasians, codes for a functionally inactive factor-B product, whereas the BF*SM allele (found in a single Chinese individual), like other alleles of BF, codes for a functionally active product. HLA haplotype analyses in individuals carrying the rarer alleles of BF revealed not only a strong association between BF*F1 and HLA-B18 and BF*S1 and HLA-Bw50 but an even stronger association between these BF alleles and alleles of the two C4 loci. BF*F1 occurred most frequently on a C4A*3,B*Q0 haplotype, whereas the BF*S1 allele was usually found on a C4A*2,B*1/B*Q0 haplotype. HLA haplotypes carrying the BF*FM and BF*SM alleles all carried the more common C*4A3,B*1 haplotype.

Alleles↗

PubMed1990

DNA polymorphism of major histocompatibility complex class II and class III genes in systemic lupus erythematosus.

We investigated the Taq I digested DNA restriction fragment length polymorphism (RFLP) of the Major Histocompatibility Complex (MHC) class II genes: HLA-DRB, -DQA, and the class III genes: C4 and 21-hydroxylase(CYP21) in 56 caucasoid patients with systemic lupus erythematosus (SLE) and 62 control subjects in order to define the molecular variation of these genes and their association with SLE. The results showed that the gene frequencies of both HLA-DR2 and -DR3 were significantly increased in the SLE population compared to normal subjects (DR2: 21.4% vs 10.7% chi 2 = 4.5. DR3: 29.6% vs 13.3%; chi 2 = 8.3). A high frequency of C4A and CYP21A gene deletions was also found in SLE patients (SLE 52%, normals 24%). All of 22 SLE patients, and 12 of 15 normal subjects who had C4A and CYP21A gene deletions had a 10.0kb Taq 1 DRB RFLP attributable to the presence of HLA-DR3. Family studies showed linkage of C4A/CYP21A deletions with HLA-B8 and -DR3, and confirmed the previously demonstrated association of the HLA-B8, DR3, C4A*Q0, C4*B1, Bf*S, C2*C haplotype with SLE. Deletions affecting the C4A and CYP21A genes were the commonest cause of C4A null alleles in SLE. No strong association between C4 null phenotype or C4 gene deletion, as determined by RFLP, was observed in patients who possessed DR2.

Complement C4↗

PubMed1994

Association of complement C4 and HLA-DR alleles with systemic lupus erythematosus in Koreans.

OBJECTIVE: To examine the association of complement C4 and HLA-DR to systemic lupus erythematosus (SLE) susceptibility in Korea. METHODS: Complement C4 protein typing was carried out by immunofixation and immunoblotting methods using EDTA-plasma from 60 patients with SLE and 72 healthy controls. Restriction fragment length polymorphism analysis of C4 genes was also carried out using TaqI or HindIII for restriction enzymes. HLA-DR was determined by polymerase chain reaction amplification with sequence specific primers using genomic DNA from 67 patients with SLE and 72 healthy controls. RESULTS: The frequency of the C4AQ0 allele was significantly higher in the patients with SLE than in controls (41.7 vs 25.0%, p < 0.05). The deletion of the C4A gene commonly found in Caucasian patients with SLE was not observed in any patients. For HLA-DR, a significant increase of the haplotype DRB1*1501 was observed in the patients (26.9 vs 12.5%, p < 0.05) and DR9 was also significantly increased (23.9 vs 11.1%, p < 0.05). An increase in each DR2 and DR9 was independent of an increase in C4AQ0. The frequencies of DR2 and DR9 were significantly decreased in patients with renal involvement and alopecia, respectively. CONCLUSION: Our data suggested that the presence of C4AQ0 allele, DRB1*1501-DRB5*0101 haplotype and DR9 contributed to susceptibility to SLE in Koreans and that Korean SLE is based on a different genetic background from Caucasian patients.

Adult↗

PubMed1993

Different manifestations of the antiphospholipid antibody syndrome in a family with systemic lupus erythematosus.

OBJECTIVE: Familial associations of the antiphospholipid antibody syndrome (APS) offer the opportunity to study genetic mechanisms of autoantibody production and disease, but are unusual. We identified a family, including identical twins and their mother, in which all members had systemic lupus erythematosus (SLE) and presented with different manifestations of the APS. METHODS: Review of case histories and clinical laboratory results, antiphospholipid antibody (aPL) studies, complement C4 protein and gene analysis, and HLA typing of family members were performed. RESULTS: Each of the 3 family members presented with a different clinical association of the APS. These various clinical presentations were closely temporally related. No particular aPL activity could be separated out that would account for the different manifestations, although the twin with thrombocytopenia and livedo reticularis had a strikingly high IgM anticardiolipin antibody level. C4A or C4B deficiencies could not be implicated in the autoimmune process. However, the mother and the twins shared the HLA haplotype that included the class II antigens DR4, DRw53, and DQw7, which has previously been associated with aPL production. CONCLUSION: This family study emphasizes the different clinical associations of aPL production in SLE. In addition to genetic influences that appear to include HLA class II antigens, the clinical presentations also suggest an environmental trigger.

Adolescent↗

PubMed2005

Confirmation of the association of the C4B null allelle in autism.

The objective of this study was to examine and attempt to confirm our previous findings of an increased frequency of the C4B null allele (C4BQ0) in subjects with autism. Newly identified subjects from Utah and Oregon were studied. Families evaluated included 85 who had a child with autism and 69 control families. Of the subjects with autism studied, 42.4% carried at least one C4BQ0, compared with 14.5% of the control subjects (p = 0.00013), with a relative risk of 4.33. Over half of the C4B null alleles in the subjects with autism involved C4A duplications. A marked increase in the ancestral haplotype 44.1 that lacks a C4B gene and has 2 C4A genes was also observed. The results of this study suggest that the human leukocyte antigen class III C4BQ0 significantly increases the risk for autism.

Autistic Disorder↗

PubMed1998

Characterization of non-expressed C4 genes in a case of complete C4 deficiency: identification of a novel point mutation leading to a premature stop codon.

The genetic basis of complete C4 deficiency in a patient with SLE was investigated. Previous studies have demonstrated that this patient has two different major histocompatibility complex (MHC) haplotypes that each contain a major deletion and a non-expressed C4 gene. In the present study, non-expression of the C4 genes was explained by the finding of two distinct C4 gene mutations. A previously described two base pair insertion in exon 29 of the C4 gene was detected in the paternal MHC haplotype [HLA-A2, B40, SC00, DR6]. The maternal haplotype [HLA-A30, B18, F1C00, DR3] carried a C4 gene with a one base pair deletion in exon 20 generating a premature stop codon. This mutation was neither found in 10 individuals with known non-expressed C4 genes nor in 9 individuals homozygous for the complotype F1C30. The isotype and allotype specific regions of the patient's C4 genes were sequenced, and both contained C4A3a sequence. In conclusion, two different MHC haplotypes resembling the extended haplotypes [HLA-A2, B40, SC02, DR6] and [HLA-A30, B18, F1C30, DR3] both contained a non-expressed C4A gene that was due to either of two distinct mutations, demonstrating the heterogeneous genetic background of C4 deficiency.

Adult↗

PubMed1989

C4 and Bf phenotypes in black and Caucasian patients with childhood onset insulin dependent diabetes mellitus.

Certain alleles for the complement proteins, C4 and Bf, have been shown to be markers for insulin-dependent diabetes mellitus (IDDM) in samples of different racial and geographic composition. However, the same markers are not demonstrable in each group studied. Phenotyping for the complement alleles, C4 and Bf was performed on 168 Caucasian and 49 Black patients with IDDM. All of the patients were followed in Memphis, Tennessee and had onset of disease prior to age 18. The Bf*F1 allelic frequency was significantly increased for the Caucasian patients as compared to 93 healthy Caucasian controls (0.063 vs. 0.016) and for the Black IDDM patients as compared to 43 healthy Black controls (0.102 vs. 0.035). C4 phenotype frequencies showed a significant increase of the C4AQ0 (rr = 2.13) and C4A4 (rr = 2.91) phenotypes for the Caucasian IDDM patients as compared to controls, but the frequency of homozygous null C4A was not significantly increased. In addition significant negative associations of IDDM with C4A3 and C4A6 phenotypes and no association with any C4B phenotype were observed in our Caucasian patient population. Our data for Mild-South Blacks with IDDM suggest a similar positive association of IDDM with the BfF1 phenotype (rr = 3.4). However, there was no evidence among Black IDDM patients of the C4AQ0 and C4A4 associations observed in the Caucasian sample. The data support a possible association of IDDM with the C4A2 (rr = 5.86) and C4B2 (rr = 5.26) phenotypes. The hypothesis that racial admixture may account for the higher frequency of IDDM in US Blacks as compared with African Blacks has been forwarded by others.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed2003

Complete sequencing and expression of three complement components, C1r, C4 and C1 inhibitor, of the classical activation pathway of the complement system in rainbow trout Oncorhynchus mykiss.

Three complement components, C1r, C4 and C1 inhibitor, of the classical activation pathway have been fully sequenced and their expression investigated in rainbow trout (Oncorhynchus mykiss). Trout C1r cDNA encodes a 707-amino-acid (aa) protein with a theoretical M(r) of 77,200. The trout translation shows highest homology with carp C1r/s, and lower, equal homologies to mammalian C1r and C1s, and MASPs from other vertebrate species. However, phylogenetic analysis and structural features suggest that the trout sequence, together with the two carp sequences, are the orthologues of mammalian C1r. The trout C4 cDNA encodes a 1,724-aa protein with a theoretical M(r) of 192,600. The trout translation shows higher homologies to the carp C4B and medaka C4, but lower homologies to C4 from other species and the carp C4A. It has a predicted signal peptide of 22 aa, a alpha-chain of 773 aa, a beta-chain of 635 aa and a lambda-chain of 288 aa. Trout C1 inhibitor cDNA encodes a 611-aa protein with a theoretical M(r) of 68,700. The trout translation has a C-terminal serpin domain with high homologies with mammalian counterparts (~37% identities), and a longer N-terminus, with no significant homology to other serpins, which contains two Ig-like domains. A molecule containing two Ig-like domains followed by a serpin domain, has also been found in an EST clone from another bony fish, the Japanese flounder. This suggests a unique structural feature of C1 inhibitor in fish. The functional significance of the Ig domains is discussed. The liver is the major site of expression of the three trout complement components, C1r, C4 and C1 inhibitor, although their expression is also detectable in other tissues. The extra-hepatic expression of complement genes may be important for local protection and inflammatory responses. Low-level constitutive expression of the three components was also detectable in a trout monocyte/macrophage cell line RTS-11, but only the expression of C4 could be upregulated by LPS.

Amino Acid Sequence↗

PubMed1985

Another family with a silent allele of properdin factor B polymorphism (BF QO).

In five of eight members of a three generation family the existence of a silent allele of the properdin factor B polymorphism (BF QO) was indicated by immunofixation of BF electrophoretic variants and by the hemolytic overlay after isoelectric focusing of BF allotypes. This was further supported by the results of HLA-A, B, C, DR, C2, C4A, C4B, GLO-typing. BF protein was decreased in all heterozygous BF deficient family members. The absolute hemolytic activity, however, was obviously compensated for by an increased relative functional activity of the normal S or F alleles on the other chromosome.

Alleles↗

PubMed2003

C5L2, a nonsignaling C5A binding protein.

C5a anaphylatoxin, a potent inflammatory mediator, is known to act through a specific G protein coupled receptor. However, some of the complex effects of C5a in vivo may not be explained solely by the deletion of the known receptor. Here, we show that an orphan receptor, identified as C5L2, is a high affinity C5a binding protein. Unlike the previously described C5aR, C5L2 is obligately uncoupled from heterotrimeric G proteins, in part by virtue of an amino acid alteration in the so-called DRY sequence at the end of the third transmembrane segment. Both human and murine C5L2 bear a leucine for arginine replacement at this site. C5L2, when transfected into several cell types, is weakly phosphorylated in transfected cells following binding of C5a but does not induce significant activation of MAP kinases, mediate calcium flux, or stimulate chemotaxis. Bone marrow cells from wild type respond robustly to C5a with induction and suppression of a number of inflammation related genes. In contrast, C5a receptor deficient mice, which bear C5L2 alone, do not respond to C5a with changes in gene transcription by microarray analyses. Biophysical properties of the C5L2, including slow ligand on and off rates, absence of internalization, and relatively high affinity for the C5a des Arg metabolite, suggest that this receptor may serve to modulate C5a biological functions in vivo. Finally, in contrast to previous reports, we find absolutely no interaction of C5L2 with other anaphylatoxins C3a and C4a.

Amino Acid Sequence↗

PubMed1991

A restriction fragment of the C2 gene is a unique marker for C2 deficiency and the uncommon C2 allele C2*B (a marker for type 1 diabetes).

There are three common C2 protein alleles in caucasians, C2*C, C2*B, and C2*Q0, with allele frequencies of 0.96, 0.03, and 0.01, as well as Sst I RFLP variants of 2.75, 2.7, 2.65, 2.55, and 2.4 kb, with frequencies of 0.017, 0.533, 0.358, 0.017, and 0.075. Thus, C2*C is informatively split by the RFLP. Of 94 nonrandomly ascertained caucasian complotypes, 77 contained C2*C, four contained C2*Q0, and 13 had C2*B. None of the C2*C-containing complotypes carried the 2.75 kb Sst I fragment and all of the complotypes with C2*B or C2*Q0 carried it. All of the C2*Q0 alleles were associated with C4A*4, C4B*2 in the complotype S042 as previously reported. C2*B was usually (9/13) in the complotype SB42, occasionally (1/13 each) in SB45, SB41, SB(4,3)0, and SB31. Thus, the association of the C2 2.75-kb fragment was with C2*B and C2*Q0, not with C4A*4, C4B*2, or even C4A*4 alone. The complotype SC42 was associated with the 2.65-kb Sst I fragment in four of five instances and in a single example with the 2.7-kb fragment. C2*B and C2*Q0 possibly had a common evolutionary ancestor complotype which carried the 2.75-kb Sst I fragment, and BF*S, C4A*4, and C4B*2. C2*B (particularly as the haplotype HLA-Bw62, SB42, DR4) is associated with type 1 diabetes but C2*Q0 is protective.

Alleles↗