Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The triplication of a region of chromosome 21 around D21S55 in 21q22.2-22.3 has been involved in the main features of Down syndrome including mental retardation (Down syndrome chromosome region: DCR). To improve the physical map of this region, we screened yeast artificial chromosome (YAC) libraries with ETS2 and ERG sequences. Five selected clones were analyzed by AluPCR, pulsed-field gel electrophoresis, and in situ hybridization. A 1.2-Mg contig, encompassing the protooncogenes ETS2 and ERG, was identified, its restriction map established and compared to the genomic map. ERG is distal to D21S55 and proximal to ETS2. ERG and ETS2 genes are 400 kb apart and in opposite orientations. The contig contains the distal boundary and part of the DCR. Three putative HTF islands were identified.
 ...
PMID:Mapping the Down syndrome chromosome region. Establishment of a YAC contig spanning 1.2 megabases. 806 51

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.
 ...
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

Down syndrome is the most frequent genetic cause of mental retardation, having an incidence of 1 in 700 live births. In the present study we used a transgenic mouse in vivo library consisting of 4 yeast artificial chromosome (YAC) transgenic mouse lines, each bearing a different fragment of the Down syndrome critical region 1 (DCR-1), implicated in brain abnormalities characterizing this pathology. The 152F7 fragment, in addition to genes also located on the other DCR-1 fragments, bears the DYRK1A gene, encoding for a serine-threonine kinase. The neurobehavioral analysis of these mouse lines showed that DYRK1A overexpressing 152F7 mice but not the other lines display learning impairment and hyperactivity during development. Additionally, 152F7 mice display increased brain weight and neuronal size. At a biochemical level we found DYRK1A overexpression associated with a development-dependent increase in phosphorylation of the transcription factor FKHR and with high levels of cyclin B1, suggesting for the first time in vivo a correlation between DYRK1A overexpression and cell cycle protein alteration. In addition, we found an altered phosphorylation of transcription factors of CREB family. Our findings support a role of DYRK1A overexpression in the neuronal abnormalities seen in Down syndrome and suggest that this pathology is linked to altered levels of proteins involved in the regulation of cell cycle.
 ...
PMID:Transgenic mouse in vivo library of human Down syndrome critical region 1: association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration. 1519 22

Down syndrome occurs every 1/1000 births and is the most frequent genetic cause of mental retardation. The genetic substrate of Down syndrome, an extra chromosome 21, was discovered by Lejeune, half-a-century ago, and the chromosome has been fully sequenced, although the gene(s) implicated in the mental retardation observed with the syndrome are still unknown. Observations of patients with partial trisomy of the 21q22.2 fragment suggest that most of the signs of the syndrome, including mental retardation, could be influenced by the region referred to as the Down Minimal Chromosomal Region-1 (DCR-1) for that reason. Using the extensive syntenies between human chromosome 21 and murine chromosome 16, Smith et al. (1995, 1997) developed transpolygenic mice with human chromosome 21 fragments covering the DCR-1. Here, we explored cognitive performances in mice over-expressing the genes carried by these fragments with the Morris water-maze and fear-conditioning procedures. The 152F7 transpolygenic mice had lower performance levels, compared to non-transgenic and other transgenic mice on most measurements in the water-maze. In fear-conditioning, all transgenic mice recorded lower performance levels compared to controls in the altered context stage. The 230E8, 141G6 and 285E6 mice failed to learn or react when the sound used as the conditional stimulus was added. These results showed that the 152F7 region played a crucial role in cognitive impairment, supporting the hypothesis of DYRK-1A gene involvement. However, the data presented here also suggest that other chromosomal regions within the DCR-1 may be involved in specific cognitive functions.
 ...
PMID:Functional analysis of genes implicated in Down syndrome: 1. Cognitive abilities in mice transpolygenic for Down Syndrome Chromosomal Region-1 (DCR-1). 1552 May 13

The association between atypical laterality and mental retardation has been reported several times, particularly in Down syndrome (DS). We investigated common genetic correlates of these components of the syndrome, examining direction (number of right paw entries in the Collins test) and degree (absolute difference between the number of right paw entries and the number of left paw entries) in mice that had incorporated extra-contiguous HSA21 fragments covering DCR-1 (Down Chromosomal Region-1). As corpus callosum size is substantially reduced in DS, and as the structure has been suspected of playing a role in atypical laterality, we also measured the corpus callosum in these mice. Extra copies of two regions (F7 and E6) have been associated with an atypical degree of laterality (strongly reduced degree). Extra copies of E8, G6 and E6 are also linked to the reduced size of the corpus callosum, indicating that the abnormal number of fibers linking the two hemispheres is not associated with atypical laterality in DS. Together, these results indicate that some of the genes involved in atypical laterality and in the reduced size of the corpus callosum in DS are present on DCR-1. An extra copy of F7 and, to a lesser extent, an extra copy of E6, are also associated with cognitive impairment. These results support the hypothesis of common genetic correlates in atypical laterality and mental retardation in DS.
 ...
PMID:Functional analysis of genes implicated in Down syndrome: 2. Laterality and corpus callosum size in mice transpolygenic for Down syndrome chromosomal region -1 (DCR-1). 1586 48

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.
 ...
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.
 ...
PMID:New cerebellar phenotypes in YAC transgenic mouse in vivo library of human Down syndrome critical region-1. 1796 26