Pfc

Xp11.4—p11.2

"Regulators of complement activation (RCA) gene cluster. "Membrane attack complex (MAC) gene cluster CMHC class III gene region. "Surfactant protein (SP) gene cluster. "Leukocyte adhesion a (LAA) gene cluster.

'Common /3 chain for the cell adhesion molecules CR3, LFA-1, and gp150,95.

No map assignment: C1q receptor (C1QR, collectin receptor), factor D (DF), factor J (JF), C8-binding protein (C8BP, HRF).

"Regulators of complement activation (RCA) gene cluster. "Membrane attack complex (MAC) gene cluster CMHC class III gene region. "Surfactant protein (SP) gene cluster. "Leukocyte adhesion a (LAA) gene cluster.

'Common /3 chain for the cell adhesion molecules CR3, LFA-1, and gp150,95.

No map assignment: C1q receptor (C1QR, collectin receptor), factor D (DF), factor J (JF), C8-binding protein (C8BP, HRF).

Membrane attack complex (MAC) components C6, C7 and C9 on human chromosome 5

Another gene cluster of complement components was assigned recently to chromosome 5. It has been known for some time that C6 and C7 of the terminal complex are genetically linked, evidence of which was mainly derived from a case of combined C6/C7 deficiency. Whereas the C6 and C7 genes are closely linked (only about 160 kb apart), the C9 gene is located at a distance of >2.5 mb. These three genes share a number of common structural features with those of the C8 a and ¡3 chains (C8A and C8B) on chromosome 1: a central cysteine-poor region flanked by several thrombospondin, epidermal growth factor (EGF) precursor and low-density lipoprotein (LDL) receptor repeats. The genes of the MAC may have evolved by duplication and translocation from an ancestral precursor functionally related to perforin, a pore-forming protein of cytotoxic T cells.

C2, factor B and C4 as class III components of the major histocompatibility complex (MHC) on human chromosome 6

These central components of the classical and alternative pathway are encoded in a 120 kb stretch of DNA flanked by the genes of class I and II MHC antigens, HLA-A, -B, -C and -DR, -DQ and -DP, respectively. Although the C2 and BF genes differ significantly in size, they share extensive homology in the coding sequence (both are precursors of functional serine proteases) and have arisen by gene duplication. No homozygous factor B deficiency has yet been reported. Homozygous C4 deficiency is a rare condition and regularly associated with autoimmune or immune complex disease (e.g. systemic lupus erythematosus (SLE) or SLE-like disease). In contrast, about two-thirds of homozygous C2-deficient individuals appear to be healthy, although cases with SLE-like disease or bacterial infections have been described. Whereas there is only a limited polymorphism of C2 and BF, the fourth component of humans is encoded by two closely linked loci -C4A and C4B - exhibiting an extensive polymorphism with a total of more than 30 alleles. Two duplicated and functionally active C4 loci are found only in higher primates and humans. In all mammals (except for the rabbit), as well as in amphibians, the class III complement genes are located in the MHC.

Complexity of the fourth component of human complement with regard to molecular basis, functions and disease associations

For a number of reasons, human C4 is unique among all complement components with regard to its genetic basis, the subtle functional differences of isotypes and allotypes as well as its potential role in the pathogenesis of disease:

1. Human C4 has the most complex molecular basis: the C4A and C4B genes encode proteins with 99% sequence homology but clearly differ ent functions. The two isotypes differ only in a single serologic determinant defined by amino acid residues of the a-chain. A single amino acid substitution from Lys to Pro at position 1101 is responsible for an apparent molecular weight change of 2 kDa on SDS-PAGE; the change from Asp to His at position 1106 alters the hemolytic activity by three- to fourfold. Further, both loci contain so-called 'null' alleles C4Q0 (= quantitative zero), which express no detectable gene product, at remarkable high frequencies (10-20%). These 'silent' alleles are due to: deletions of an entire C4 gene including one of the adjacent genes of steroid 21-hydroxylase, CYP21 (such as C4AQ0 in the most common Caucasoid HLA haplotype Al-Cw7-B8-C2C-BFS-C4AQ0B1-DR3), gene conversion from one C4 isotype to the other (e.g. in the HLA haplotype B44-C2C-BFS-C4A3BQ0-DR4), or non-expression of structural genes due to individual point mutations (e.g. in the HLA haplotype B60-C2C-BFS-C4AQ0B2-DR6). In addition, a number of haplotypes with structurally duplicated C4 genes have been found.

2. Different functions have been ascribed to the thiolester bond of nascent C4b: C4A preferentially transacylates on to amino group nucleo-philes, whereas C4B prefers hydroxyl groups for ester formation. Furthermore, C4A is 1.7-fold more efficient at inhibiting immune precipitation than C4B. Complete C4-deficient serum has almost no neutralizing activity in a mumps virus neutralization assay; purified C4A enhances the reaction about tenfold compared with C4B. Immunization experiments with complement-deficient guinea pigs have provided evidence that both C4 isotypes play distinct roles in the induction and amplification of the T cell-dependent immune response.

3. There is a steadily growing list of associations (of variable confidence) of C4 deficiency with a wide variety of diseases such as SLE, rheumatoid arthritis, systemic sclerosis, subacute sclerosing panencephalitis (SSPE), primary biliary cirrhosis, chronic polyarthritis, multiple sclerosis, visceral leishmaniasis, chronic glomerulonephritis, leprosy, Brazilian paracoccidioidomycosis, common variable immunodeficiency, immunoglobulin A deficiency, insulin-dependent diabetes mellitus, Chagas disease and the acquired immune deficiency syndrome (AIDS). A number of autoimmune diseases are associated with the HLA haplotype Al-Cw7-B8-C4AQ0B1-DR3.

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