RESUMO
Even though the molecular mechanisms underlying the Down syndrome (DS) phenotypes remain obscure, the characterization of the genes and conserved non-genic sequences of HSA21 together with large-scale gene expression studies in DS tissues are enhancing our understanding of this complex disorder. Also, mouse models of DS provide invaluable tools to correlate genes or chromosome segments to specific phenotypes. Here we discuss the possible contribution of HSA21 genes to DS and data from global gene expression studies of trisomic samples.
Assuntos
Cromossomos Humanos Par 21/genética , Síndrome de Down/genética , Perfilação da Expressão Gênica , Animais , Modelos Animais de Doenças , Humanos , Camundongos , FenótipoRESUMO
Even though the molecular mechanisms underlying the Down syndrome (DS) phenotypes remain obscure, the characterization of the genes and conserved non-genic sequences of HSA21 together with large-scale gene expression studies in DS tissues are enhancing our understanding of this complex disorder. Also, mouse models of DS provide invaluable tools to correlate genes or chromosome segments to specific phenotypes. Here we discuss the possible contribution of HSA21 genes to DS and data from global gene expression studies of trisomic samples.
Embora os mecanismos moleculares que causam a síndrome de Down (SD) não sejam totalmente conhecidos, a caracterização de genes e seqüências não gênicas conservadas do HSA21 e os estudos de expressão em grande escala em amostras de pacientes com SD estão aumentando o entendimento da síndrome. Por outro lado, os modelos murinos da SD provêm ferramentas valiosas para correlacionar genes ou segmentos cromossômicos a características fenotípicas específicas. Nesta revisão, são discutidas as possíveis contribuições dos genes do HSA21 à SD e os dados de estudos de expressão gênica global de amostras trissômicas.
Assuntos
Animais , Humanos , Camundongos , /genética , Síndrome de Down/genética , Perfilação da Expressão Gênica , Modelos Animais de Doenças , FenótipoRESUMO
We used immunocytochemical and fluorescence assays to investigate the subcellular location of the protein encoded by Down syndrome critical region gene 2 (DSCR2) in transfected cells. It was previously suggested that DSCR2 is located in the plasma membrane as an integral membrane protein. Interestingly, we observed this protein in the endoplasmic reticulum (ER) of cells. We also studied whether the truncated forms of DSCR2 showed different subcellular distributions. Our observations indicate that DSCR2 probably is not inserted into the membrane of the endoplasmic reticulum since the fragments lacking the predicted transmembrane (TM) helices remained associated with the ER. Our analyses suggest that, although DSCR2 is associated with the endoplasmic reticulum, it is not an integral membrane protein and it is maintained on the cytoplasmic side of the ER by indirect interaction with the ER membrane or with another protein.
Assuntos
Síndrome de Down/genética , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Musculares/metabolismo , Animais , Células CHO , Células COS , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Retículo Endoplasmático/ultraestrutura , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Fluorescência Verde/genética , Humanos , Imuno-Histoquímica , Proteínas de Membrana/genética , Proteínas de Membrana/ultraestrutura , Chaperonas Moleculares , Proteínas Musculares/genética , Proteínas Musculares/ultraestrutura , Mutagênese Sítio-Dirigida , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Deleção de SequênciaRESUMO
The Down's syndrome candidate region 1 (DSCR1) protein, encoded by a gene located in the human chromosome 21, interacts with calcineurin and is overexpressed in Down's syndrome patients. As an approach to clarifying a putative function for this protein, in the present study we used the yeast two-hybrid system to identify DSCR1 partners. The two-hybrid system is a method that allows the identification of protein-protein interactions through reconstitution of the activity of the yeast GAL 4 transcriptional activator. The gene DSCR1 fused to the GAL 4 binding domain (BD) was used to screen a human fetal brain cDNA library cloned in fusion with the GAL 4 activation domain (AD). Three positive clones were found and sequence analysis revealed that all the plasmids coded for the ubiquitously expressed transcript (UXT). UXT, which is encoded in human Xp11, is a 157-amino acid protein present in both cytosol and nucleus of the cells. This positive interaction of DSCR1 and UXT was confirmed in vivo by mating the yeast strain AH109 (MATa) expressing AD-UXT with the strain Y187 (MATalpha) expressing BD-DSCR1, and in vitro by co-immunoprecipitation experiments. These results may help elucidate a new function for DSCR1 and its participation in Down's syndrome pathogenesis.
Assuntos
Inibidores de Calcineurina , Síndrome de Down/metabolismo , Proteínas Musculares/metabolismo , Proteínas de Neoplasias/metabolismo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Calcineurina/fisiologia , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/metabolismo , Síndrome de Down/genética , Eletroforese em Gel de Ágar , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Chaperonas Moleculares , Proteínas Musculares/genética , Proteínas de Neoplasias/genética , Mapeamento de Interação de Proteínas , Transdução de Sinais , Fatores de TranscriçãoRESUMO
The Down's syndrome candidate region 1 (DSCR1) protein, encoded by a gene located in the human chromosome 21, interacts with calcineurin and is overexpressed in Down's syndrome patients. As an approach to clarifying a putative function for this protein, in the present study we used the yeast two-hybrid system to identify DSCR1 partners. The two-hybrid system is a method that allows the identification of protein-protein interactions through reconstitution of the activity of the yeast GAL 4 transcriptional activator. The gene DSCR1 fused to the GAL 4 binding domain (BD) was used to screen a human fetal brain cDNA library cloned in fusion with the GAL 4 activation domain (AD). Three positive clones were found and sequence analysis revealed that all the plasmids coded for the ubiquitously expressed transcript (UXT). UXT, which is encoded in human Xp11, is a 157-amino acid protein present in both cytosol and nucleus of the cells. This positive interaction of DSCR1 and UXT was confirmed in vivo by mating the yeast strain AH109 (MATa)expressing AD-UXT with the strain Y187 (MATalfa) expressing BD-DSCR1, and in vitro by co-immunoprecipitation experiments. These results may help elucidate a new function for DSCR1 and its participation in Down's syndrome pathogenesis.