RESUMO
Among full autosomal trisomies, only trisomies of chromosome 21 (Down syndrome), 18 (Edwards syndrome) and 13 (Patau syndrome) are compatible with postnatal survival. But the mechanisms, how a supernumerary chromosome disrupts the normal development and causes specific phenotypes, are still not fully explained. As an alternative to gene dosage effect due to the trisomic chromosome a genome-wide transcriptional dysregulation has been postulated. The aim of this study was to define the transcriptional changes in trisomy 13, 18, and 21 during early fetal development in order to obtain more insights into the molecular etiopathology of aneuploidy. Using oligonucleotide microarrays, we analyzed whole genome expression profiles in cultured amniocytes (AC) and chorionic villus cells (CV) from pregnancies with a normal karyotype and with trisomies of human chromosomes 13, 18 and 21. We observed a low to moderate up-regulation for a subset of genes of the trisomic chromosomes. Transcriptional levels of most of the genes on the supernumerary chromosome appeared similar to the respective chromosomal pair in normal karyotypes. A subset of chromosome 21 genes including the DSCR1 gene involved in fetal heart development was consistently up-regulated in different prenatal tissues (AC, CV) of trisomy 21 fetuses whereas only minor changes were found for genes of all other chromosomes. In contrast, in trisomy 18 vigorous downstream transcriptional changes were found. Global transcriptome analysis for autosomal trisomies 13, 18, and 21 supported a combination of the two major hypotheses.
Assuntos
Cromossomos Humanos/genética , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Transcrição Gênica , Trissomia/genética , Âmnio/citologia , Âmnio/metabolismo , Células Cultivadas , Vilosidades Coriônicas/metabolismo , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 21/genética , Feminino , Perfilação da Expressão Gênica , Genes Controladores do Desenvolvimento , Humanos , Gravidez , Análise de Componente Principal , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Lambda-producing B lymphocytes have frequently deleted one or, more often, both Ig kappa loci. This deletion is mediated by the rearrangement of an element which lies 3' of C kappa and which is called RS (recombining sequence) in the mouse and Kde (kappa-deleting element) in the human. The tight correlation between V lambda to J lambda rearrangements and an RS-mediated deletion may indicate that sequences in the C kappa-RS region are controlling the activation of the Ig lambda locus. We have linked the C kappa exon and the RS element by phage cloning and compared the C kappa-RS region to the previously cloned human C kappa-Kde region. The distance between C kappa and RS is 25 kb and is thus similar to the distance of 24 kb separating the human C kappa exon and Kde element. Both mouse and man carry a conserved sequence of 470 bp (Rx) which lies 9 kb 3' of the mouse C kappa and 12 kb 3' of the human C kappa exon. The conserved mouse Rx sequence contains part of the kappa 3' enhancer.
Assuntos
Rearranjo Gênico de Cadeia Leve de Linfócito B/imunologia , Regiões Constantes de Imunoglobulina/genética , Cadeias kappa de Imunoglobulina/genética , Animais , Sequência de Bases , Camundongos , Dados de Sequência Molecular , Recombinação Genética/genética , Mapeamento por RestriçãoRESUMO
The antigen receptors on mature B lymphocytes are membrane-bound immunoglobulins of the IgM and IgD classes whose cross-linking by polyvalent antigens results in B-cell proliferation and differentiation. How these membrane-bound immunoglobulin chains, which lack a cytoplasmic tail, generate a cell activation signal is not at present known. We now show that the IgM molecule is non-covalently associated in the membrane of B cells with two proteins of relative molecular mass 34,000 (Mr 34 K; IgM-alpha) and 39 K (Ig-beta) which form a disulphide-linked heterodimer. Surface expression of IgM seems to require the formation of an appropriate complex between IgM and the heterodimer. A transfection experiment indicates that IgM-alpha is the product of mb-1, a B-cell specific gene encoding a transmembrane protein with sequence homology to proteins of the T-cell antigen receptor-CD3 complex.