Disease relevance of C4A

• C4 polymorphism and major histocompatibility complex haplotypes in IgA deficiency: association with C4A null haplotypes [1].
• Rare variant of complement C4 is seen in high frequency in patients with primary glomerulonephritis [2].
• A group of patients with Type 1 (insulin-dependent) diabetes mellitus was investigated for HLA-A, B and DR antigens as well as C4 and factor B polymorphism [3].
• HLA-linked complement markers in Alzheimer's and Parkinson's disease: C4 variant (C4B2) a possible marker for senile dementia of the Alzheimer type [4].
• Complement component 4 (C4) is an important plasma protein playing a major role in the human defense mechanism against infectious diseases and inflammatory processes [5].

Psychiatry related information on C4A

• We previously reported that the complement C4B null allele appears to be associated with infantile autism [6].
• We compared the frequency of various C4B types in 25 patients with familial Alzheimer dementia (AD), 22 patients with sporadic AD, and 360 control individuals [7].
• We describe, for the first time, evidence for the existence of a C-4 hydroxylation pathway in the metabolism of bile acids, which may be unique to early human development [8].

High impact information on C4A

• DNA polymorphism of the C4 genes. A new marker for analysis of the major histocompatibility complex [9].
• C4 genomic polymorphisms are inherited with the segment of the short arm of chromosome 6 that carries the HLA-DR and complement loci [9].
• We conclude that a DNA-protein complex involving 100 bp and terminating with the C4A4 repeat can be sufficient to provide the fundamental functions of telomeres, allowing linear DNA replication and conferring stability of linear DNA [10].
• The short DNA molecules of the macronucleus are terminated with repeats of the octanucleotide C4A4 [11].
• Inability to activate the classical complement pathway, abnormal kinetics of alternative-pathway activation and depressed antibody responses to a T-cell-dependent antigen may predispose C4-deficient patients to viral infection or immune-complex formation [12].

Chemical compound and disease context of C4A

• This report deals with the genetic factors involved in insulin-dependent diabetes mellitus (IDD) in The Netherlands. Twenty-two Dutch multiplex families with IDD were typed for HLA-A, -B, -C, and -DR antigens, for BF, C2, C4, and GLO polymorphisms, as well as for GM allotypes of immunoglobulins [13].
• Complement C4 null alleles as a marker of gold or D-penicillamine toxicity in the treatment of rheumatoid arthritis [14].
• Liver biopsies of a 58-year-old clinically healthy patient with a hepatomegaly and intracisternal PAS-negative globular hyaline bodies were immunofluorescent-optically examined for the content of the complement components C 1 q, C 4, C 9, C 1-inactivator, C 3-activator [15].
• Of 26 patients with autoimmune chronic active hepatitis (CAH) starting in childhood 18 (69%) had low C4 and 5 (19%) had low C3 serum levels [16].
• Serum creatinine and proteinuria did not differ between patients with identical and C4A-dominant C4 deposition [17].

Biological context of C4A

• Eight combinations of HLA-B, DR, BF, C2, C4A, and C4B markers were found to occur in haplotypes at frequencies significantly higher than expected [18].
• Correlation between a DNA restriction fragment length polymorphism and C4A6 protein [19].
• Several disorders, including systemic lupus erythematosus and type I diabetes, show associations with C4 phenotypes [19].
• The fourth component of complement (C4) in man, is coded for by two separate but closely linked loci (C4A and C4B) within the major histocompatibility region (MHC), on the short arm of chromosome 6 [19].
• 3. However, only some C4 null alleles are due to gene deletions, the remainder were thought to be nonexpressed genes [20].

Anatomical context of C4A

• C4-specific mRNA was present at low concentrations in C4-deficient (C4D) patient fibroblasts, but no pro-C4 protein was detected [21].
• By using the technique of DNase I hypersensitivity mapping, we established that the only area of transcriptional activity for C4 in the hepatocyte cell line, HepG2, occurs approximately 500 base pairs upstream of the transcriptional start site [22].
• The covalent binding of C4 to immunoglobulins and immune complexes (IC) also enhances the solubilization of immune aggregates, and the clearance of IC through complement receptor one (CR1) on erythrocytes [23].
• Th inclusion bodies reacted with antisera against the complement components C 4, C 3 and C 3-activator, as also identified by double immunofluorescence [15].
• A human hepatoma-derived cell line (HepG2), in addition to synthesizing C4s and small quantities of the polypeptide precursor of C4 (pro-C4), was found to secrete p168 and p125 at concentrations of 14 +/- 4.8 and 21 +/- 9.2% (mean +/- SD), respectively, of total secreted C4 [24].

Associations of C4A with chemical compounds

• Extensive conservation of upstream C4 promoter sequences: a comparison between C4A and C4B [25].
• Twelve transcriptional units have now been located in a 160 kb segment of DNA that includes the genes encoding members of the serum complement system C2, Factor B (Bf) and C4 within the class III region of the human major histocompatibility complex (MHC) [26].
• Of the two critical events required for C5 cleavage, namely formation of a covalent adduct between C3b and the C4b subunit of the C3 convertase (C4b2a), and binding of C5 to this C4b-C3b complex, it is a defect in the latter step that accounts for the aberrant activity of C4A6 [27].
• Previous studies have localized the defect in C4A6 to the C5 convertase stage [27].
• The C4A and C4B isotypes of human C4 show certain functional differences that stem from their relative preference for transacylation to amino (-NH2) vs hydroxyl (-OH) nucleophiles, respectively, on complement-activating surfaces [28].

Physical interactions of C4A

• These results clearly demonstrate that C3/C4 gene duplication and linkage between the C4 gene and the major histocompatibility complex predate mammalian/amphibian divergence [29].
• In addition, the clinical observation of an increased incidence of homozygous C4A null alleles in systemic lupus erythematosus may be explained in part by defective processing of immune complexes in the absence of C4A [30].
• This corresponds well to the known ability of C-4-S to bind copper ions and is a potential mechanism by which LDL oxidation in the arterial intima is facilitated after prolonged retention by the extracellular matrix [31].

Regulatory relationships of C4A

• C4A3 is more effective than C4B1 in its capacity to inhibit the rate of immune precipitate formation in serum and in serum-free reaction mixtures containing C1 and C4 [32].
• Expression of C4A and C4B genes is regulated by IFN-gamma in human hepatoma cells and in murine fibroblasts transformed with the respective genes [33].
• Complement system protein C4 and susceptibility to hydralazine-induced systemic lupus erythematosus [34].

Other interactions of C4A

• Human populations are endowed with a sophisticated genetic diversity of complement C4 and its flanking genes RP, CYP21, and TNX in the RCCX modules of the major histocompatibility complex class III region [35].
• Characterization of a de novo conversion in human complement C4 gene producing a C4B5-like protein [36].
• As shown by definitive RFLPs, the tandemly arranged genes RP, C4, CYP21, and TNX are duplicated together as a discrete genetic unit termed the RCCX module [37].
• Extended MHC haplotypes and CYP21/C4 gene organisation in Irish 21-hydroxylase deficiency families [38].
• We did not find significant differences in Bf and C4 allotype frequencies in RA patients subdivided according to severity of the disease into a mild group and a progressive group [39].

Analytical, diagnostic and therapeutic context of C4A

• To directly ascertain whether this single substitution was responsible for the hemolytic defect in C4A6, we have used site-directed mutagenesis to introduce this change into both C4A and C4B cDNA expression plasmids [27].
• RESEARCH DESIGN AND METHODS: We determined C4 phenotypes in 241 patients with IDDM and 140 healthy control subjects by agarose gel electrophoresis and immunoprecipitation [40].
• Additionally, we have used a combination of short and long range restriction mapping procedures in order to characterize the CYP21/C4 gene organization associated with individual serologically defined haplotypes [38].
• The quantitation of the C4A/B ratio by densitometry of stained gels or by conventional immunochemical measurements of serum C4 level could not substantially improve the identification of A*Q0 or B*Q0 [41].
• C4 isotype studies were performed in plasma samples obtained before surgery, with use of agarose gel immunofixation and crossed immunoelectrophoresis [42].

References