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

Human chromosome 21 is associated with many disorders, including Down syndrome (DS). In an effort to identify genes involved in brain development or function and therefore implicated in the mental retardation associated with DS, we chose YACs from three regions of chromosome 21: a region within the so-called "Down syndrome critical region," a region proximal to it, and one distal to it. We made cosmid libraries from these YACs and generated high-resolution physical maps by constructing cosmid contigs. These are the first cosmid contigs on chromosome 21 outside the critical region. The cosmids were used for direct selection of cDNAs to isolate chromosome 21 expressed sequences. We have isolated 45 nonredundant partial cDNAs and mapped these back to the cosmid contigs. We isolated 3 nonoverlapping portions of DSCR1 and a part of GIRK2 and identified 3 nonoverlapping partial cDNAs with similarity to the rat Dyrk gene, which turned out to be the human homologue (MNB) of the Drosophila minibrain gene. Twelve sequences had matches with either STS or EST entries in the databases, including a chromosome 21 EST, a chromosome 21 STS, and 6 unmapped expressed sequence entries. Only 1 sequence resulted in a match with a protein entry. The remaining 25 sequences revealed no similarity to any database entry. All of these partial cDNAs are expressed as determined by Northern blotting or by RT-PCR.
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PMID:Cosmid contig and transcriptional map of three regions of human chromosome 21q22: identification of 37 novel transcripts by direct selection. 933 61

Two KIR (K+ Inwardly Rectifying) channel genes have been identified on chromosome 21, in a region associated with important phenotypic features of trisomy 21, including mental retardation: KIR3.2 (GIRK2) and KIR4.2. We analysed the expression of these channel genes in developing human and mouse brains to determine the possible role of the corresponding channels in brain development and function. KIR3.2, which has been extensively studied in the mouse, was found to be expressed in the human cerebellum during development. The KIR4.2 channel is expressed later in development in both mice and humans. We compared the expression of these channels in terms of RNA and protein levels and discussed the potential synergy and consequences of the overexpression of these channels in Down's syndrome brain development.
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PMID:Chromosome 21 KIR channels in brain development. 1506 43

Down Syndrome (DS, trisomy 21) is the most common genetic cause of mental retardation. The completed sequencing of genes encoded on chromosome 21 provides excellent basic information, however the molecular mechanisms leading to the phenotype of DS remain to be elucidated. Although overexpression of chromosome 21 encoded genes has been documented information at the protein expression level is mandatory as it is the proteins that carry out function. We therefore decided to evaluated expression level of seven proteins whose genes are encoded on chromosome 21: DSCR4, DSCR5, DSCR6; KIR4.2, GIRK2, KCNE1 and KCNE2 in fetal cortex brain of DS and controls at the early second trimester of pregnancy by Western blotting. beta-actin and neuron specific enolase (NSE) were used to normalise cell loss and neuronal loss. DSCR5 (PIG-P), a component of glycosylphosphatidylinositol- N-acetylglucosaminyltransferase (GPI-GnT), was overexpressed about twofold, even when levels were normalised with NSE. DSCR6 was overexpressed in addition but when normalised versus NSE, levels were comparable to controls. DSCR4 was not detectable in fetal brain. Potassium channels KIR4.2 and GIRK2 were comparable between DS and controls, whereas KCNE1 and KCNE2 were not detectable. Quantification of these proteins encoded on chromosome 21 revealed that not all gene products of the DS critical region are overexpressed in DS brain early in life, indicating that the DS phenotype cannot be simply explained by the gene dosage effect hypothesis. Overexpression of PIG-P (DSCR5) may lead to or represent impaired glycosylphosphatidylinositol- N-acetylglucosaminyltransferase mediated posttranslational modifications and subsequent anchoring of proteins to the plasma membrane.
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PMID:Protein levels of genes encoded on chromosome 21 in fetal Down Syndrome brain (Part V): overexpression of phosphatidyl-inositol-glycan class P protein (DSCR5). 1522 5

Down syndrome (DS) is the leading non-heritable cause of mental retardation and is due to the effects of an extra chromosome 21. Mouse models of DS have been developed which parallel many of the cognitive and behavioral deficits of DS individuals. Of these, Ts65Dn mice show abnormal hippocampal properties including learning and memory deficits, altered synaptic plasticity and irregular dendritic spines. We assessed synaptic function of cultured postnatal Ts65Dn hippocampal neurons through examination of spontaneous miniature excitatory post-synaptic currents (mEPSCs) and compared them to those from diploid neurons. Averaged amplitudes and frequency of mEPSC events were similar to diploid suggesting presynaptic function is not overtly disrupted in Ts65Dn hippocampal neurons. However, both averaged decay and rise times (10-90% of peak) were significantly faster (approximately 20% for both rise and decay) in Ts65Dn neurons compared to diploid. The distribution of both decay and rise times, indicates global scaling of all percentile groups and is independent of amplitude suggesting normal electrotonic filtering in spite of abnormal expression of GIRK2 channel in Ts65Dn mouse. Western blot analysis suggests overexpression of GluR4 subunit of AMPA receptors which may contribute to faster mEPSC in Ts65Dn neurons. Intrinsic synaptic properties influenced by genetics or epigenetics factors in Ts65Dn postnatal cultured neurons are therefore disrupted and may contribute to the cognitive deficits associated with DS.
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PMID:Speeding of miniature excitatory post-synaptic currents in Ts65Dn cultured hippocampal neurons. 1849 Jan 8

G protein-activated inwardly rectifying K+ channels (GIRK) generate slow inhibitory postsynaptic potentials in the brain via G(i/o) protein-coupled receptors. GIRK2, a GIRK subunit, is widely abundant in the brain and has been implicated in various functions and pathologies, such as learning and memory, reward, motor coordination, and Down syndrome. Down syndrome, the most prevalent cause of mental retardation, results from the presence of an extra maternal chromosome 21 (trisomy 21), which comprises the Kcnj6 gene (GIRK2). The present study examined the behaviors and cellular physiology properties in mice harboring a single trisomy of the Kcnj6 gene. Kcnj6 triploid mice exhibit deficits in hippocampal-dependent learning and memory, altered responses to rewards, hampered depotentiation, a form of excitatory synaptic plasticity, and have accentuated long-term synaptic depression. Collectively the findings suggest that triplication of Kcnj6 gene may play an active role in some of the abnormal neurological phenotypes found in Down syndrome.
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PMID:Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice. 2230 28