C4 is the only component of the human complement system that is coded for by two genes, C4A and C4B, showing 99% homology. The genes for the two C4 isotypes are located with the genes for the second component (C2), factor B (BF), and steroid 21-hydroxylase (21-OHA and 21-OHB) between HLA-B and -DR in the MHC on chromosome six (1-4). The C4 and 21-OH genes are tandemly arranged and have probably arisen by duplication (Fig . 1 a). Based on the direction of transcription, C4A is usually expressed at C4 locus I, whereas C4B is usually expressed at locus II (5).C4A and C4B are highly polymorphic with more than 35 alleles including null alleles (C4QO) at both loci (6). The polymorphism can be defined by electrophoretic mobility ofthe intact protein or its subunits (7-9), by serology of Rodgers (Rg) and Chido (Ch) determinants (10), and by functional studies of complement activation and binding characteristics (11,12). A sequence of four amino acids in the C4d region (Chido 4 determinant on C4B molecules) is responsible for the major structural and functional differences of the C4 isotypes (Fig. 1 c; 9, 11-13) . The antigenic determinants Rodgers and Chido are generally expressed on the C4A and C4B isotypes, respectively, but rare reversed associations have been described (14). Gene conversion has been discussed as a possible mechanism for the generation of aberrant allotypes (15,16).Null alleles of C4A or C4B (AQO or BQO) occur at frequencies of 0.1-0 .3 in the normal population (17), and are assessed by the absence of gene products. The structural analysis of the C4 genes at the DNA level has revealed that only a proportion of C4 null alleles result from gene deletions affecting an entire C4 gene and one adjacent 21-OH gene, and consequently other null alleles were due to nonexpressed genes (pseudogenes) (18,19). Alternatively, it has been suggested that null alleles represent the expression of two identical, and therefore undistinguishable, allotypes on a haplotype, and this results from gene conversion of C4A to C4B and the reverse (5, 20).
Based on evidence of an increased rate of respiratory infections in sudden infant death (SID) infants as well as the observation of familial occurrence, we analysed in a retrospective study class II and class II genes of the major histocompatibility complex in 40 cases of SID by Southern blot analysis of DNA obtained post mortem from tissue samples. In 24 cases, the parents were interviewed and confirmatory human lymphocyte antigen (HLA) and DNA typing was carried out. Using HLA-DR beta and -DQ beta probes, no evidence of an abnormal HLA-DR frequency distribution in SID infants was detected (P = 0.97). Using DNA probes for the tandemly arranged complement C4 and steroid 21-hydroxylase genes, an increased number of C4B gene deletions in SID cases was found. The increase in C4 gene deletions was significant (P = 0.0125) in infants with recurrent infections. These data indicate a possible role of partial C4 deficiency as a genetically predisposing risk factor in SID.
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