Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Oligophrenin-1 is a recently discovered Rho-GTPase activating protein, mutation of which is associated with X-linked mental retardation. Since little is known about the cellular localization of oligophrenin-1 in central and peripheral neurons, we investigated its expression by RT-PCR and immunochemical analysis. Oligophrenin-1 immunoreactivity was found in glial cells forming myelin sheaths in the vagus nerve, sciatic nerve and dorsal roots of guinea-pig, rat and human, in chromaffin cells of the adrenal medulla, and in chromaffin cells associated with sympathetic ganglia. No immunoreactivity was detected in sympathetic neurons, in glial cells surrounding these neurons, in optic nerve or in spinal cord myelin. The full length cDNA sequence was determined from guinea-pig sciatic nerve. The translated amino acid sequence was 99% identical to the published human oligophrenin-1 sequence. Western blotting revealed two protein forms which were expressed to different relative extents in different tissues. A 91 kDa form was predominant in extracts of sciatic nerve whereas a 36 kDa form was relatively more abundant in adrenal medulla and brain. Greater amounts of the full length oligophrenin-1 protein occurred in the sciatic nerve of adult rats, compared with P2 rats, which reflects the development of myelination. The presence of multiple forms does not appear to be due to alternative mRNA splicing since RT-PCR products amplified from a variety of tissues were identical and only a single mRNA transcript of 7.4 kb was identified by Northern analysis. These findings demonstrate that a major site of oligophrenin-1 expression is peripheral myelin.
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PMID:Evidence that a major site of expression of the RHO-GTPASE activating protein, oligophrenin-1, is peripheral myelin. 1502 18

Of 11 genes involved in nonspecific X-linked mental retardation (MRX), three encode regulators or effectors of the Rho GTPases, suggesting an important role for Rho signaling in cognitive function. It remains unknown, however, how mutations in Rho-linked genes lead to MRX. Here we report that oligophrenin-1, a Rho-GTPase activating protein that is absent in a family affected with MRX, is required for dendritic spine morphogenesis. Using RNA interference and antisense RNA approaches, we show that knock-down of oligophrenin-1 levels in CA1 neurons in rat hippocampal slices significantly decreases spine length. This phenotype can be recapitulated using an activated form of RhoA and rescued by inhibiting Rho-kinase, indicating that reduced oligophrenin-1 levels affect spine length by increasing RhoA and Rho-kinase activities. We further demonstrate an interaction between oligophrenin-1 and the postsynaptic adaptor protein Homer. Our findings provide the first insight into how mutations in a Rho-linked MRX gene may compromise neuronal function.
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PMID:The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. 1503 83

This review is focused on pathways and mechanisms that might provide molecular links between the pathogenesis of renal and pulmonary disease in tuberous sclerosis complex and the pathogenesis of the neurologic manifestations of tuberous sclerosis complex. Tuberous sclerosis complex is an autosomal dominant disorder in which the manifestations can include seizures; mental retardation; autism; benign tumors of the brain, retina, skin, and kidneys; and pulmonary lymphangiomyomatosis. Lymphangiomyomatosis is a life-threatening lung disease affecting almost exclusively young women. Genetic data have demonstrated that the cells giving rise to renal angiomyolipomas, the most frequent tumor type in patients with tuberous sclerosis complex, exhibit differentiation plasticity. Genetic studies have also shown that the benign smooth muscle cells of angiomyolipomas and pulmonary lymphangiomyomatosis have the ability to migrate or metastasize to other organs. These findings indicate that hamartin and tuberin play functional roles in the regulation of cell migration and differentiation. The biochemical pathways responsible for these effects are not yet fully understood but might involve dysregulation of the small guanosine triphosphatase Rho. Similar pathways might contribute to aberrant neuronal differentiation and migration in tuberous sclerosis complex.
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PMID:Aberrant cellular differentiation and migration in renal and pulmonary tuberous sclerosis complex. 1556 18

For several decades it has been known that mental retardation is associated with abnormalities in dendrites and dendritic spines. The recent cloning of eight genes which cause nonspecific mental retardation when mutated, provides an important insight into the cellular mechanisms that result in the dendritic abnormalities underlying mental retardation. Three of the encoded proteins, oligophrenin1, PAK3 and alphaPix, interact directly with Rho GTPases. Rho GTPases are key signaling proteins which integrate extracellular and intracellular signals to orchestrate coordinated changes in the actin cytoskeleton, essential for directed neurite outgrowth and the generation/rearrangement of synaptic connectivity. Although many details of the cell biology of Rho signaling in the CNS are as yet unclear, a picture is unfolding showing how mutations that cause abnormal Rho signaling result in abnormal neuronal connectivity which gives rise to deficient cognitive functioning in humans.
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PMID:Rho proteins, mental retardation and the neurobiological basis of intelligence. 1558 14

This review focuses on the 19 identified genes involved in X-linked "non-syndromic" mental retardation (MR) and defines the signaling pathways in which they are involved, focusing on emerging common mechanisms. The majority of proteins are involved in three distinct pathways: (1) Rho GTPases pathway modulating neuronal differentiation and synaptic plasticity; (2) Rab GTPases pathway regulating synaptic vesicle cycling; (3) gene expression regulation. The function of four proteins (ACSL4, AT2, SLC6A8, and SAP102) could not be reconciled to a common pathway. From a clinical point of view, the review discusses whether some common dysmorphic features can be identified even in non-syndromic MR patients and whether it is correct to maintain the distinction between "non-syndromic" and "syndromic" MR.
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PMID:Non-syndromic X-linked mental retardation: from a molecular to a clinical point of view. 1569 Mar 97

Three of seven recently identified genes mutated in nonsyndromic mental retardation are involved in Rho family signaling. Two of the gene products, alpha-p-21-activated kinase (PAK) interacting exchange factor (alphaPIX) and PAK3, form a complex with the synaptic adaptor protein G-protein-coupled receptor kinase-interacting protein 1 (GIT1). Using an RNA interference approach, we show that GIT1 is critical for spine and synapse formation. We also show that Rac is locally activated in dendritic spines using fluorescence resonance energy transfer. This local activation of Rac is regulated by PIX, a Rac guanine nucleotide exchange factor. PAK1 and PAK3 serve as downstream effectors of Rac in regulating spine and synapse formation. Active PAK promotes the formation of spines and dendritic protrusions, which correlates with an increase in the number of excitatory synapses. These effects are dependent on the kinase activity of PAK, and PAK functions through phosphorylating myosin II regulatory light chain (MLC). Activated MLC causes an increase in dendritic spine and synapse formation, whereas inhibiting myosin ATPase activity results in decreased spine and synapse formation. Finally, both activated PAK and activated MLC can rescue the defects of GIT1 knockdown, suggesting that PAK and MLC are downstream of GIT1 in regulating spine and synapse formation. Our results point to a signaling complex, consisting of GIT1, PIX, Rac, and PAK, that plays an essential role in the regulation of dendritic spine and synapse formation and provides a potential mechanism by which alphaPIX and PAK3 mutations affect cognitive functions in mental retardation.
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PMID:A GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. 1580 Jan 93

Many forms of mental retardation and cognitive disability are associated with abnormalities in dendritic spine morphology. Visualization of spines using live-imaging techniques provides convincing evidence that spine morphology is altered in response to certain forms of LTP-inducing stimulation. Thus, information storage at the cellular level appears to involve changes in spine morphology that support changes in synaptic strength produced by certain patterns of synaptic activity. Because the structure of a spine is determined by its underlying actin cytoskeleton, there has been much effort to identify signaling pathways linking synaptic activity to control of actin polymerization. This review, part of the TINS Synaptic Connectivity series, discusses recent studies that implicate EphB and NMDA receptors in the regulation of actin-binding proteins through modulation of Rho family small GTPases.
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PMID:Spine architecture and synaptic plasticity. 1580 52

A consistent feature of neurons in patients with mental retardation is abnormal dendritic structure and/or alterations in dendritic spine morphology. Deficits in the regulation of the dendritic cytoskeleton affect both the structure and function of dendrites and synapses and are believed to underlie mental retardation in some instances. In support of this, there is good evidence that alterations in signaling pathways involving the Rho family of small GTPases, key regulators of the actin and microtubule cytoskeletons, contribute to both syndromic and nonsyndromic mental retardation disorders. Because the Rho GTPases have been shown to play increasingly well-defined roles in determining dendrite and dendritic spine development and morphology, Rho signaling has been suggested to be important for normal cognition. The purpose of this review is to summarize recent data on the Rho GTPases pertaining to dendrite and dendritic spine morphogenesis, as well as to highlight their involvement in mental retardation resulting from a variety of genetic mutations within regulators and effectors of these molecules.
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PMID:Rho GTPases, dendritic structure, and mental retardation. 1588 2

Mutations in the Pak3 gene lead to nonsyndromic mental retardation characterized by selective deficits in cognition. However, the underlying mechanisms are yet to be elucidated. We report here that the knock-out mice deficient in the expression of p21-activated kinase 3 (PAK3) exhibit significant abnormalities in synaptic plasticity, specifically hippocampal late-phase long-term potentiation, and deficiencies in learning and memory. A dramatic reduction in the active form of transcription factor cAMP-responsive element-binding protein in the knock-out mice implicates a novel signaling mechanism by which PAK3 and Rho signaling regulate synaptic function and cognition.
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PMID:Abnormal long-lasting synaptic plasticity and cognition in mice lacking the mental retardation gene Pak3. 1601 25

It is still unclear why absence of the fragile X protein (FMRP) leads to mental retardation and specific behavioral problems. In neurons, the protein transports specific mRNAs towards the actively translating ribosomes near the synapses. To unravel the mechanism leading to the disorder, we performed global gene expression analysis by means of the differential display method using the fragile X mouse model. To verify differential expression, we used microarray technology and real-time PCR. Three differentially expressed cDNAs showed consistent underexpression in the fragile X knockout mouse, including a GABA(A) receptor subunit delta, a Rho guanine exchange factor 12 and an EST BU563433. In addition, we identified 5 genes that showed differential expression dependent on the sample of RNA analysis. We consider their differential expression as provisional. It is possible that these differentially expressed genes play an important role in the cognitive and behavioral problems observed in the fragile X syndrome.
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PMID:Expression profiling suggests underexpression of the GABA(A) receptor subunit delta in the fragile X knockout mouse model. 1619 66


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