RESUMO
Human Ig heavy chain constant regions are encoded by a cluster of genes, the IGHC locus, on 14q32.3. Several forms of IGHC deletions and duplications spanning one to five genes have been described in different populations, with frequencies of 1.5-3.5% and 4.5-44%, respectively. Despite the common occurrence of these gene rearrangements, little is known about the breakpoint sites; evidence obtained from deletions in the IGHC locus and in other regions of the human genome suggests that they preferentially occur in highly homologous regions and might be favored by a variety of recombinogenic signals. We present here a detailed study of three homozygotes for the most common type of IGHC multiple gene deletion, spanning the A1-GP-G2-G4-E genes. Using a combination of Southern blotting, long-range PCR, and automated sequencing, the unequal crossover events of all of the six studied haplotypes have been mapped to a region of approximately 2 kb with almost complete homology between EP1-A1 and E-A2, flanked by two minisatellites. These results are consistent with the hypothesis that segments of complete homology may be required for efficient homologous recombination in humans. The possible role of minisatellites as recombination signals is inferred, in agreement with current knowledge.
Assuntos
Deleção de Genes , Rearranjo Gênico de Cadeia Pesada de Linfócito B/genética , Cadeias Pesadas de Imunoglobulinas/genética , Família Multigênica/imunologia , Southern Blotting , Mapeamento Cromossômico , Troca Genética/imunologia , Homozigoto , Humanos , Cadeias alfa de Imunoglobulina/genética , Cadeias épsilon de Imunoglobulina/genética , Cadeias gama de Imunoglobulina/genética , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Mapeamento por Restrição , Análise de Sequência de DNARESUMO
The molecular bases of classical serological immunoglobulin allotypes are progressively uncovered through detailed characterization of the relevant genes. Here we describe two isoallotypic determinants of the G4 gene. In the first, Leu 309, as in G1 and G3, is changed to Val, as in G2; studies on myeloma proteins have long assigned the immunologically defined nG4 m(a)/(b) to the same position. The two molecular variants, here called IGHG4*L309 and IGHG4*V309, are allelic in IGHC haplotypes with a single G4 gene, but can be found together in cis in G4-duplicated haplotypes. A second isoallotypic variant was found at codon 409, where either Arg, as in G1 and G3, or Lys, as in G2, can be found. Both isoallotypes are associated with several 'silent isoallotypic' substitutions dispersed through the hinge, CH2 and CH3 domains. This suggests segmental gene conversion as the common mechanism of origin.
Assuntos
Alótipos de Imunoglobulina/genética , Imunoglobulina G/genética , Sequência de Bases , DNA , Feminino , Genes de Imunoglobulinas , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo GenéticoRESUMO
Development of a second lymphoma after autotransplantation is an unusual event. Its real incidence, however, could be underestimated, since histologic and immunophenotyping techniques are often unable to distinguish it from a relapse. We report a lymphoma patient in apparent relapse after 42 months of molecular remission achieved by autotransplantation. Sequencing analysis of the immunoglobulin heavy-chain genes showed that the rearrangement of variable, diversity and joining segments had changed between diagnosis and relapse and suggested that a second lymphoma had developed.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Linfoma de Burkitt/diagnóstico , Rearranjo Gênico , Genes de Imunoglobulinas , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma Folicular/terapia , Segunda Neoplasia Primária/diagnóstico , Adulto , Sequência de Bases , Humanos , Masculino , Dados de Sequência Molecular , Recidiva , Transplante AutólogoRESUMO
The structure of the human immunoglobulin heavy chain constant region (IGHC), on chromosome 14q32, comprises nine CH genes and two pseudogenes, all originating from multiple duplication events. Continuing evolution of the region is demonstrated by the finding of various types of duplicated and deleted haplotypes, which together add up to 6%. Here we provide molecular and genetic evidence that the G4 gene is duplicated in 44% of IGHC haplotypes in the Italian population. The duplication spans about 20 kb of genomic DNA and probably originated through unequal crossing over. Refined characterisation of the genomic region downstream from the G4 gene improves our knowledge of the evolutionary history of CH genes.
Assuntos
Genes de Imunoglobulinas , Haplótipos , Regiões Constantes de Imunoglobulina/genética , Cadeias Pesadas de Imunoglobulinas/genética , Família Multigênica , Southern Blotting , Cromossomos Humanos Par 14/genética , Clonagem Molecular , Eletroforese em Gel de Campo Pulsado , Frequência do Gene , Humanos , Itália , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Polimorfismo GenéticoRESUMO
The therapeutical effectiveness of L 105, a new drug preparation exhibiting antidiarrhoeal activity and containing Rifaxidin, was tested on 22 patients with acute gastroenteric syndrome of bacterial aetiology. In all patients there was a prompt restoration of intestinal function by the 2nd treatment day. Both local and systemic drug tolerance proved to be good in all cases.
