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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mental retardation represents the more invalidating pathological aspect of Down syndrome, DS, and has a hard impact in public health. Modifications in DS brain, concerning abnormal size, neuronal differentiation, and cell density, cause changes in the neurophysiology and behavior of DS patients, and could be determined by dosage imbalance of genes localized in the DS critical region, DCR. Among these genes, C21orf5 showed high homology with Caenorhabditis elegans Pad1 involved in cellular differentiation and patterning. To shed light on C21orf5 role in DS, we performed molecular characterization of human and mouse orthologs, their spatio-temporal expression during development and in adult, and overexpression in DS and transgenic mice. C21orf5 was widely expressed early in embryogenesis in the nervous system. Later, its expression became differential and increased in mesencephalon and rhomboencephalon. This developmental expression profile evolves selectively in adult brain with higher signals in hippocampus, cerebellum, perirhinal, and entorhinal cortex, compared to the other cortical regions. Cellular specificity was detected in hippocampus with higher C21orf5 mRNA level in CA3 cells. Our findings appoint C21orf5 as candidate gene for mental retardation: Its overexpression in DS cells may contribute to gene imbalance in DS.Its specific expression in normal and its mirroring pattern in transgenic mice correspond to abnormal regions in DS patients and to neurological phenotype of transgenic mice. Altered cortical lamination in transgenic mice and the Pad1 ortholog function suggest a potential role of C21orf5 in cell differentiation. Its patterned differential expression in the medial temporal-lobe system, including hippocampal formation and perirhinal cortex involved in memory storage, and learning and memory defects in the transgenic mice suggest a specialized role for C21orf5 in cognitive processes. These evidences suggest that C21orf5 is an attractive candidate gene contributing to neurological alterations responsible for mental retardation in DS patients.
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PMID:The differentially expressed C21orf5 gene in the medial temporal-lobe system could play a role in mental retardation in Down syndrome and transgenic mice. 1276 18

Mental retardation represents the more invalidating pathological aspect of trisomy 21 and has a hard impact on public health. The dosage imbalance of chromosome 21 genes could be the cause of neurological alterations and mental retardation seen in Down syndrome. We studied C21orf5 that we have demonstrated to be overexpressed in Down syndrome tissues, as a candidate gene for trisomy 21. A new optical technology (Rachidi et al., 2000) was used to compare signal intensity and cell density in presumptive embryonic brain compartments, at their boundaries and in higher specialized brain centres during fetal lifespan. We showed a developmentally regulated transcriptional activity of C21orf5 and a regional and cellular specific distribution of gene transcripts during human embryonic and fetal development. A wide but differential expression was detected in the nervous system during embryogenesis with a relatively lower level in the forebrain than in the midbrain and hindbrain and the highest transcription intensity in the future cerebellum. This developmentally regulated expression is maintained during post-embryogenesis and evolves selectively in fetal cerebral, hippocampal and cerebellar areas. Differential and cellular specificity were detected in hippocampus with higher C21orf5 mRNA level in the pyramidal cells compared to granular cells of the dentate gyrus. The expression pattern detected in cortical and cerebellar structures correlates well to the altered cortical lamination and to the lower size of the cerebellum observed in Down syndrome patients. In addition, the patterned differential expression detected in the medial temporal-lobe system, including hippocampal formation and perirhinal cortex, working as control centres of the memory circuits and involved in cognitive processes and memory storage, also corresponds to abnormal brain regions seen in Down syndrome patients. The C21orf5 selective expression in the key brain structures for learning and memory suggests that C21orf5 overexpression could participate in mental retardation pathogenesis in Down syndrome patients.
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PMID:C21orf5, a human candidate gene for brain abnormalities and mental retardation in Down syndrome. 1627 86

Availability of the human genome sequence promises important progress in the understanding of human pathologies, particularly for multifactorial diseases. Among these, Down syndrome (DS) is the most frequent genetic cause of mental retardation. A critical region of chromosome 21, the Down syndrome Chromosomal Region-1 (DCR-1), is responsible for many features of the DS phenotype including mental retardation. We studied DCR-1 C21orf5 as a new candidate gene for DS considering its restricted expression in key brain regions altered in DS patients and involved in learning and memory processes. To elucidate C21orf5 molecular function, we performed a comparative study of protein sequences in several species and showed that C21orf5 represents a new member of the Dopey leucine zipper-like family. The C21orf5 C-termini contains two highly conserved leucine-like zipper domains in invertebrate and vertebrate species. Evolution analysis indicated a common ancestral origin of these protein sequences also suggesting a conserved function of this gene throughout phylogenesis. Mutations of the known C21orf5 homologous genes Aspergillus nidulans DopA, Saccharomyces cerevisiae Dop1 and Caenorhabditis elegans pad1, determine morphological abnormalities. We studied transgenic mice carrying the human C21orf5 gene and we showed that this gene is overexpressed in brain regions by in situ hybridization and by real-time RT-PCR experiments. Interestingly, we also showed that these transgenic mice have an increased density of cortical cells overexpressing C21orf5. Similarly, DS patients have an altered lamination pattern in their cortex. Considering together our and previous findings, we suggest that the human dopey family member, C21orf5, could play a role in brain morphogenesis and, when overexpressed, it could participate in neurological features and mental retardation observed in DS patients.
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PMID:C21orf5, a new member of Dopey family involved in morphogenesis, could participate in neurological alterations and mental retardation in Down syndrome. 1630 51

Down syndrome (DS) is the most frequent genetic cause of mental retardation (MR) associated with neurological alterations. To allow a genetic dissection of DS phenotype, we studied eight transgenic mouse lines carrying YACs containing human DNA fragments covering DS critical region (DCR-1), as an in vivo library. Herein, we found an increased brain size in the 152F7-mice containing DYRK1A gene. We also identified a new cerebellar alteration in two independent lines carrying 230E8-YAC. These mice showed significant elongation of the cerebellar antero-posterior axis (p<0.001), determined by increased length of rostral folia of the vermis (lobule II-V, p<0.0001; lobule VI, p<0.001). In addition, we identified a major neurological defect in culmen and declivus lobules in the 230E8-mice. We analyzed P30, P12, and P9 stages and detected high significant increased lengths of anterior lobules (II-VI) of 230E8-mice at P30 and P12 (lobule II-V, p<0.0001; lobule VI, p<0.05), but not at P9, indicating that this new phenotype appears between P9 and P12. Interestingly, 230E8-mice also present increased cortical cell density and mild learning defects. 230E8-YAC contains seven genes, some of which could be potentially responsible for this phenotype. Between them, we proposed DOPEY2 as potential candidate gene for these cerebellar alterations considering its high expression in the brain and that its homologous genes in yeast, Caenorhabditis elegans and Drosophila are involved in morphogenesis, suggesting a conserved role of DOPEY2 as a patterning gene.
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PMID:New cerebellar phenotypes in YAC transgenic mouse in vivo library of human Down syndrome critical region-1. 1796 26

The brain alterations and mental retardation in Down syndrome are associated with overdosage of chromosome 21 genes. To shed light on the understanding of the molecular effect of this genetic overdosage, gene expression studies have crucial importance to quantify expression variations in Down syndrome tissues compared to normal ones. Herein, an in situ Quantitative Assessment of Gene Expression (QAGE) was used to quantify and statistically analyze, for the first time, DOPEY2 expression variations in different regions of the Down syndrome human fetal brains and to compare them to corresponding normal brains. DOPEY2, which is localized in the Down Syndrome Critical Region (DSCR) and is a candidate gene for neurological alterations in Down syndrome, showed a delimited regional and cellular expression pattern in the cortex, hippocampus and cerebellum, characterized by different transcriptional intensities in both normal and trisomic brains. DOPEY2 is overexpressed more than 50% (1.79-, 1.97- and 2.12-folds in the cortex, cerebellum and hippocampus, respectively), and showed statistically significant differences in the overexpression ratios in the three brain regions expressing DOPEY2. The demonstration of differential DOPEY2 expression and overexpression in human fetal brains suggests that this gene is submitted to a complex transcriptional control and could depend from other human chromosome 21 genes. Moreover, DOPEY2 overexpression in the brain regions, that are altered in Down syndrome patients and involved in learning and memory processes, is in agreement to the hypothesis that this gene plays a potential role in functional brain alterations and in the pathogenesis of mental retardation in Down syndrome. This new in situ QAGE approach allowed quantitative measurements of transcriptional changes and statistical evaluations of the expression and overexpression patterns of DOPEY2 at specific regions of the brain, which is a complementary approach to qRT-PCR and microarray for transcriptome study. Moreover, this approach could be a powerful tool to study the candidate chromosome 21 genes for Down syndrome and other pathologies caused by regionalized quantitative transcriptional alterations, for greater interpretation of functional processes driving gene expression.
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PMID:A quantitative assessment of gene expression (QAGE) reveals differential overexpression of DOPEY2, a candidate gene for mental retardation, in Down syndrome brain regions. 1946 Jun 34