The locus for human immunoglobulin heavy chain constant region genes (IgCH) is characterized by a significant frequency of deleted or duplicated haplotypes, due to unequal crossing-over events. Four types of deletions and one duplication have been reported so far. We describe here a molecular study of four cases of IgCH deletions. Two of the three types of deletions are reported here for the first time. Analysis of genetic markers associated with the deleted haplotypes pointed to the independent origin of similar deletions and the involvement of intergenic sequences in the mispairing-recombination process. The reduced or absent transcription of the C gamma 4 gene in two C gamma 2-deleted haplotypes offers an insight into the requirements for the isotype switch mechanism.

Human immunoglobulin heavy chain constant region (IGHC) genes constitute a typical multigene family, usually comprising eleven genes on the telomere of chromosome 14 (14q32). In this region, deleted and duplicated haplotypes have been reported to exist with considerable frequency. Their origin is the result of either unequal crossing-over or looping out excision. In this paper, we report the characterization of a new type of deletion, involving the IGHG4 gene, in a subject who also carries a larger deletion of a previously described type on the second chromosome. Employment of several methods (polymerase chain reaction, standard Southern blot, pulsed field gel electrophoresis, serological techniques) to analyze these deleted haplotypes has resulted in a level of accuracy in their characterization that has not been achieved in previous cases. The site of recombination responsible for the IGHG4 deletion was restricted to a 2.5-kb region 3' of the G4 gene; this rules out any possible involvement of the S regions in the recombination process. The usefulness of the various techniques in the characterization of the deletions is also discussed, together with possible future applications in the field.

The human immunoglobulin heavy chain constant region locus (IGHC) comprises nine genes and two pseudogenes clustered in a 350 kilobase (kb) region on chromosome 14q32. Several IGHC haplotypes with single or multiple gene deletions and duplications have been characterized. The most likely mechanism accounting for these unusual haplotypes is the unequal crossing-over between homologous regions within the locus. Here we report the analysis of an unusual case of familial clustering of deletions/duplications. In the two branches of the BON family, three duplicated and two deleted haplotypes, all probably independent in origin, have been characterized. The structure of the haplotypes, one of which is described here for the first time, supports the hypothesis of homologous unequal crossing-over as the origin of recombinant haplotypes. The analysis of serological markers in a subject carrying one deleted and one duplicated haplotype allowed us the first direct inferences concerning the functions of the duplicated IGHC haplotypes.

The human immunoglobulin heavy chain constant gene locus (IGHC) is polymorphic at both the protein (Gm and A2m allotypes) and the DNA level [RFLP for the gamma genes (IGHG), the switch mu region (IGHSM) and the switch alpha regions (IGHSA)]. The polymorphisms have been a valuable tool for assessment of the IGHC locus organization and a variety of population genetics and immunological investigations. In this study three new probes, identifying regions related to the IGHG (IGHPG and IGHSG) or IGHA (IGHAT) genes, have been employed to describe 11 different loci, 6 of which were polymorphic. Most of the polymorphisms are probably due to short insertions/deletions, particularly the SG regions, due to their repetitive structure. Ten loci were assigned to the IGHC region on the basis of known restriction maps, deletion mapping and association with mapped RFLP; the 11th, despite a striking sequence similarity with the IGHPG regions, could not be assigned to any known IGHC subregion. Analysis of these and previously known IGHG RFLP in a sample of 65 unrelated subjects plus 15 families allowed us to draw a genetic map, with particularly high resolution in the GP-G2-G4 genes region, revealing a marked discontinuity in the linkage disequilibrium values between pairs of adjacent loci.

No abstract