Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute hyperammonemia (HA) causes cerebral edema and brain damage in children with urea cycle disorders (UCDs) and in patients in acute liver failure. Chronic HA is associated with developmental delay and mental retardation in children with UCDs, and with neuropsychiatric symptoms in patients with chronic liver failure. Astrocytes are a major cellular target of hyperammonemic encephalopathy, and changes occurring in these cells are thought to be causally related to the brain edema of acute HA. To study the effect of HA on astrocytes in vivo, we crossed the Otc(spf) mouse, a mouse with the X-linked UCD ornithine transcarbamylase (OTC) deficiency, with the hGFAP-EGFP mouse, a mouse selectively expressing green fluorescent protein in astrocytes. We used FACS to purify astrocytes from the brains of hyperammonemic and healthy Otcspf/GFAP-EGFP mice. RNA isolated from these astrocytes was used in microarray expression analyses and qRT-PCR. When compared with healthy littermates, we observed a significant downregulation of the gap-junction channel connexin 43 (Cx43) the water channel aquaporin 4 (Aqp4) genes, and the astrocytic inward-rectifying potassium channel (Kir) genes Kir4.1 and Kir5.1 in hyperammonemic mice. Aqp4, Cx43, and Kir4.1/Kir5.1 are co-localized to astrocytic end-feet at the brain vasculature, where they regulate potassium and water transport. Since, NH4+ ions can permeate water and K+-channels, downregulation of these three channels may be a direct effect of elevated blood ammonia levels. Our results suggest that alterations in astrocyte-mediated water and potassium homeostasis in brain may be key to the development of the brain edema.
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PMID:Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. 1818 79

Developmental thyroid hormone (TH) deficiency leads to mental retardation and neurological deficits in humans. In this study, congenital hypothyroidism was induced in rats by adding 0.05% 6-propyl-2-thiouracil in the drinking water during gestation and suckling period. This treatment induced hyperphosphorylation of neurofilaments, the neuronal intermediate filament (IF) proteins, of heavy, medium and low molecular weight (NF-H, NF-M and NF-L, respectively) without altering the phosphorylation level of astrocyte IF proteins, glial fibrillary acidic protein (GFAP) and vimentin in cerebral cortex of rats. NF-H was hyperphosphorylated on KSP repeats in the carboxy-terminal tail domain. Furthermore, the immunocontent of GFAP and NF subunits was down-regulated, while vimentin was unaltered both in tissue homogenate and in cytoskeletal fraction of hypothyroid animals. Moreover, we verified the immunocontent of astrocyte glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) as well as activation of mitogen-activated protein kinases (MAPKs) in hypothyroid rats. Results showed that hypothyroidism is associated with decreased GLAST and GLT-1 immunocontent. Additionally, we demonstrated increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation without altering Jun N-terminal kinase (JNK) and p38(MAPK) phosphorylation. However, total JNK levels were down-regulated. Taken together, these results suggest that the thyroid status could modulate the integrity of neuronal cytoskeleton acting on the endogenous NF-associated phosphorylating system and that such effect could be related to glutamate-induced excitotoxicity, as well as ERK1/2 and JNK modulation. These events could be somehow related to the neurological dysfunction described in hypothyroidism.
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PMID:Congenital hypothyroidism is associated with intermediate filament misregulation, glutamate transporters down-regulation and MAPK activation in developing rat brain. 1884 85

The Hyderabad Metropolitan Area had 562 lakes at one time, but only 162 now remain. These are polluted to various degrees and pose environmental and health hazards. The Hussain Sagar Lake provided water for irrigation and drinking until 1930 and supported aquatic life till 1976. It is now contaminated by organic chemicals discharged by many industrial estates in its basin. An estimated 28,190 cmum of industrial effluents and domestic sewage are let into it daily. Phenols, benzenes, cyanides, and toxic metals make it poisonous. The ground water around the lake is also polluted. The polluted lakes ruin vegetable farms, kill fetuses in the womb, and cause mental retardation, still births, and infertility. In the city's outskirts, clinically confirmed cancer is 11 times higher and heart ailments 16 times more than elsewhere. The Hyderabad Urban Development Authority (HUDA) took up a Lake Conservation and Restoration Project as part of its Green Environment Program in 2002. Several lakes have been restored by setting up effluent (or sewage) treatment plants. HUDA also built lake parks with recreation facilities and environment education centers. HUDA also organized jointly with the World Water Institute, Pune, India, an international workshop on urban lake conservation and management in June 2003. It adopted the Hyderabad Declaration which, among other things, states the worthy aim of restoring all the water bodies by 2009. Even if it takes a few more years, the restoration of all the polluted lakes will usher in multiple benefits to Hyderabad citizens.
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PMID:From poison ponds to pleasure spots. 1899 11

Our computer simulations of gamma glutamyl semialdehyde dehydrogenase (GGSALDH, pyrroline 5-carboxylate dehydrogenase, ALDH4) were initiated from the Thermus thermophilus crystal structures in an effort to understand the effects of a seemingly subtle mutation. In humans, a natural S352L mutation gives rise to type II hyperprolinemia (mental retardation). The mutation occurs in what might be a priori considered the outer shell of the active site, affecting a residue of no obvious significance. In another member of the superfamily (ALDH3) this serine residue is an aspartate, which tethers the "distal" Lys. It has been our hypothesis that in ALDH3 this is a beneficial interaction, enabling the "proximal" Lys to interact with the carbonyl oxygen of the peptide bond with the catalytic Cys, allowing the Cys amide N to transiently protonate the tetrahedral intermediate. That the role of this Asp is significant is proved by a natural Asp-to-Asn mutation that abolishes activity. The Ser-to-Leu exchange in GGSALDH might be expected to alter the water structure at the site of mutation, and the MM simulations clearly support this. It was our hypothesis, based on initial static models of the mutation, that the leucyl side chain would block the direct or indirect interaction of the distal Lys with the active site. Our simulations indicate that this lysine residue is indeed important in explaining the molecular pathology of the mutation. Through small rotations of its C-C bonds, the Lys epsilon-amino group comes into H-bonding distance with Ser-326, the equivalent of human Ser-352. In the S326L mutant, this interaction is not possible, while the water network from this residue to the target main-chain carbonyl oxygen is disturbed as well.
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PMID:Gamma glutamyl semialdehyde dehydrogenase: simulations on native and mutant forms support the importance of outer shell lysines. 1900 Jun 60

Germline mutations in SPRED1, a negative regulator of Ras, have been described in a neurofibromatosis type 1 (NF1)-like syndrome (NFLS) that included learning difficulties in some affected individuals. NFLS belongs to the group of phenotypically overlapping neuro-cardio-facial-cutaneous syndromes that are all caused by germ line mutations in genes of the Ras/mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) pathway and that present with some degree of learning difficulties or mental retardation. We investigated hippocampus-dependent learning and memory as well as synaptic plasticity in Spred1(-/-) mice, an animal model of this newly discovered human syndrome. Spred1(-/-) mice show decreased learning and memory performance in the Morris water maze and visual-discrimination T-maze, but normal basic neuromotor and sensory abilities. Electrophysiological recordings on brain slices from these animals identified defects in short- and long-term synaptic hippocampal plasticity, including a disequilibrium between long-term potentiation (LTP) and long-term depression in CA1 region. Biochemical analysis, 4 h after LTP induction, demonstrated increased ERK-phosphorylation in Spred1(-/-) slices compared with those of wild-type littermates. This indicates that deficits in hippocampus-dependent learning and synaptic plasticity induced by SPRED1 deficiency are related to hyperactivation of the Ras/ERK pathway.
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PMID:Spred1 is required for synaptic plasticity and hippocampus-dependent learning. 1911 78

While the function of dystrophin in muscle disease has been thoroughly investigated, dystrophin and associated proteins also have important roles in the central nervous system. Many patients with Duchenne and Becker muscular dystrophies (D/BMD) have cognitive impairment, learning disability, and an increased incidence of some neuropsychiatric disorders. Accordingly, dystrophin and members of the dystrophin-associated glycoprotein complex (DGC) are found in the brain where they participate in macromolecular assemblies that anchor receptors to specialized sites within the membrane. In neurons, dystrophin and the DGC participate in the postsynaptic clustering and stabilization of some inhibitory GABAergic synapses. During development, alpha-dystroglycan functions as an extracellular matrix receptor controlling, amongst other things, neuronal migration in the developing cortex and cerebellum. Several types of congenital muscular dystrophy caused by impaired alpha-dystroglycan glycosylation cause neuronal migration abnormalities and mental retardation. In glial cells, the DGC is involved in the organization of protein complexes that target water-channels to the plasma membrane. Finally, mutations in the gene encoding epsilon-sarcoglycan cause the neurogenic movement disorder, myoclonus-dystonia syndrome implicating epsilon-sarcoglycan in dopaminergic neurotransmission. In this review we describe the recent progress in defining the role of the DGC and associated proteins in the brain.
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PMID:The neurobiology of the dystrophin-associated glycoprotein complex. 1917 27

Underground water in many regions of the world is contaminated with high concentrations of arsenic and the resulting toxicity has created a major environmental and public health problem in the affected regions. Chronic arsenic exposure can cause many diseases, including various physical and psychological harms. Although the physical problems caused by arsenic toxicity are well reported in literature, unfortunately the consequences of arsenic exposure on mental health are not adequately studied. Therefore we conducted a review of the available literature focusing on the social consequences and detrimental effects of arsenic toxicity on mental health. Chronic arsenic exposures have serious implications for its victims (i.e. arsenicosis patients) and their families including social instability, social discrimination, refusal of victims by community and families, and marriage-related problems. Some studies conducted in arsenic affected areas revealed that arsenic exposures are associated with various neurologic problems. Chronic arsenic exposure can lead to mental retardation and developmental disabilities such as physical, cognitive, psychological, sensory and speech impairments. As health is defined by the World Health Organization as "a state of complete physical, mental and social wellbeing", the social dimensions have a large impact on individual's mental health. Furthermore studies in China und Bangladesh have shown that mental health problems (e.g. depression) are more common among the people affected by arsenic contamination. Our study indicates various neurological, mental and social consequences among arsenic affected victims. Further studies are recommended in arsenic-affected areas to understand the underlying mechanisms of poor mental health caused by arsenic exposure.
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PMID:A systematic review of arsenic exposure and its social and mental health effects with special reference to Bangladesh. 1954 9

Fragile X syndrome (FXS), a common form of inherited mental retardation, is caused by the lack of fragile X mental retardation protein (FMRP). The animal model of FXS, Fmr1 knockout mice, have deficits in the Morris water maze and trace fear memory tests, showing impairment in hippocampus-dependent learning and memory. However, results for synaptic long-term potentiation (LTP), a key cellular model for learning and memory, remain inconclusive in the hippocampus of Fmr1 knockout mice. Here, we demonstrate that FMRP is required for glycine induced LTP (Gly-LTP) in the CA1 of hippocampus. This form of LTP requires activation of post-synaptic NMDA receptors and metabotropic glutamateric receptors, as well as the subsequent activation of extracellular signal-regulated kinase (ERK) 1/2. However, paired-pulse facilitation was not affected by glycine treatment. Genetic deletion of FMRP interrupted the phosphorylation of ERK1/2, suggesting the possible role of FMRP in the regulation of the activity of ERK1/2. Our study provide strong evidences that FMRP participates in Gly-LTP in the hippocampus by regulating the phosphorylation of ERK1/2, and that improper regulation of these signaling pathways may contribute to the learning and memory deficits observed in FXS.
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PMID:Fragile X mental retardation protein is required for chemically-induced long-term potentiation of the hippocampus in adult mice. 1965 72

PQBP1 (polyglutamine tract-binding protein 1) is a causative gene for a relatively frequent X-linked syndromic and non-syndromic mental retardation (MR). To analyze behavioral abnormalities of these patients from molecular basis, we developed a knock-down (KD) mouse model. The KD mice possess a transgene expressing 498 bp double-strand RNA that is endogenously cleaved to siRNA suppressing PQBP1 efficiently. After confirming that PQBP1 is selectively suppressed to nearly 50% of the control mice, we performed behavioral analyses of PQBP1-KD mice. The KD mice possessed normal ability in ordinary memory tests including water-maze test, whereas they showed abnormal anxiety-related behavior in light/dark exploration test and open-field test and showed obvious declines of anxiety-related cognition in the repetitive elevated plus maze or novel object recognition test. Correspondingly, we found c-fos upregulation and histone H3 acetylation after behavior tests were declined in neurons of amygdala, prefrontal cortex and hippocampus. Furthermore, we found that 4-phenylbutyric acid, an HDAC inhibitor, efficiently improved expression of these genes and rescued the abnormal phenotypes in adult PQBP1-KD mice. These results suggested that PQBP1 dysfunction in regulating gene expression might underlie the abnormal behavior and cognition of PQBP1-KD mice and that the recovery of expression of such PQBP1 target genes might improve the symptoms in adult patients.
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PMID:Knock-down of PQBP1 impairs anxiety-related cognition in mouse. 1966 Nov 83

Biotin is a water-soluble vitamin that serves as an essential coenzyme for five carboxylases in mammals. Biotin-dependent carboxylases catalyze the fixation of bicarbonate in organic acids and play crucial roles in the metabolism of fatty acids, amino acids and glucose. Carboxylase activities decrease substantially in response to biotin deficiency. Biotin is also covalently attached to histones; biotinylated histones are enriched in repeat regions in the human genome and appear to play a role in transcriptional repression of genes and genome stability. Biotin deficiency may be caused by insufficient dietary uptake of biotin, drug-vitamin interactions and, perhaps, by increased biotin catabolism during pregnancy and in smokers. Biotin deficiency can also be precipitated by decreased activities of the following proteins that play critical roles in biotin homeostasis: the vitamin transporters sodium-dependent multivitamin transporter and monocarboxylate transporter 1, which mediate biotin transport in the intestine, liver and peripheral tissues, and renal reabsorption; holocarboxylase synthetase, which mediates the binding of biotin to carboxylases and histones; and biotinidase, which plays a central role in the intestinal absorption of biotin, the transport of biotin in plasma and the regulation of histone biotinylation. Symptoms of biotin deficiency include seizures, hypotonia, ataxia, dermatitis, hair loss, mental retardation, ketolactic acidosis, organic aciduria and also fetal malformations. This review focuses on the deficiencies of both biotin and biotinidase, and the medical management of such cases.
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PMID:Biotin and biotinidase deficiency. 1972 38


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