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

Neurofibromatosis type 1 (NF1) or von Recklinghausen neurofibomatosis, is a common heritable neurocutaneous disorder. This disorder appears to affect all races, with a prevalence estimated to be 1 in 3000. Approximately half of all cases of NF1 represent new mutations. The characteristics of NF1, which include cafe-au-lait spots, neurofibromas, Lisch nodules, optic glioma, osseous lesions, macrocephaly, short stature and mental retardation suggest that the genetic lesion affects the proper development of multiple organ systems. Within the past few years, the gene causing NF1 has been identified and the protein encoded by this gene, neurofibromin, has been the subject of detailed investigation. The NF1 gene spans over 350 kb of genomic DNA and encodes a protein product of 2818 amino acids. Neurofibromin is expressed in many different tissues. It is now known that one role of neurofibromin is as a GTPase activating protein (GAP), very likely in the same pathway of signal transduction as ras. Absence of neurofibromin in mice homozygously mutant for the NF1 gene results in profound developmental abnormalities. In mice that are heterozygous for NF1, an accelerated onset of tumor formation is observed. Combined with studies of tumors from NF1 patients showing homozygous deletions in the NF1 gene, these data suggest a role for NF1 as a "tumor suppressor". Evidence suggesting other roles played by neurofibromin, in control of proliferation in some situations and differentiation in others, is gradually bringing the previously hazy picture of this genetic disorder into sharper focus.
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PMID:Neurofibromatosis type 1: pathology, clinical features and molecular genetics. 767 Jun 56

Tuberous sclerosis (TSC) is an autosomal dominant trait characterized by the widespread development of benign tumours classified as hamartoma, and is often associated with seizures and mental retardation. The patchy distribution and focal nature of the growths suggests that they might result from inactivation of a tumour suppressor gene by a two-hit process. Over the last 2 years, studies designed to investigate both germline and somatic TSC mutations have lent support to this hypothesis. Analysis of TSC-associated hamartomas has shown loss of heterozygosity for the regions of chromosomes 9 and 16 known to harbour TSC genes, consistent with the occurrence of somatic 'second-hit' mutations. Parallel investigations using pulse field gel electrophoresis have identified constitutional deletions representing 'first-hit' mutations at 16p13.3, leading to the rapid identification of one of the causative genes, TSC2. Intriguingly, the TSC2 product, tuberin, has an area of sequence homology with the GTPase activating protein rap1GAP, suggesting a possible mechanism for its role in regulating cellular growth.
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PMID:The molecular genetics of tuberous sclerosis. 784 41

Tuberous sclerosis (TS) is an autosomal dominant disorder in which affected individuals manifest mental retardation, seizures, and a variety of benign and malignant tumors. The TSC2 tumor suppressor gene was recently identified by positional cloning and its protein product, tuberin, shown to represent one member of the rap GTPase activating protein (rapGAP) family. In order to determine the contribution of tuberin to the development of mental retardation and seizures in patients with TS, we examined the expression of tuberin in adult and developing nervous system tissues. Since tuberin is the second rapGAP found in the nervous system, the expression of tuberin was compared to the expression of rapGAP, rap1, and rap2. In this study, we demonstrate that tuberin is expressed at greatest levels in the spinal cord and cerebellum as opposed to rapGAP, which is not enriched in these tissues. Tuberin expression in the adult CNS is restricted to the olfactory bulb, several CNS neuronal populations, brainstem nuclei, cerebellar Purkinje cells, and motor neurons in the ventral spinal cord. In contrast, rapGAP is expressed in many different cell types in the adult CNS, but not in cerebellar Purkinje cells or motor neurons in the ventral spinal cord. However, there is significant expression of rapGAP in astrocytes. The restricted distribution of tuberin expression relative to rap1 and rapGAP suggests that tuberin may be the primary rap1 regulator in a subpopulation of CNS neurons.
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PMID:Expression of the tuberous sclerosis 2 gene product, tuberin, in adult and developing nervous system tissues. 917 18

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by a mutation in either the TSC1 or TSC2 tumour suppressor gene. The disease is characterized by a broad phenotypic spectrum that can include seizures, mental retardation, renal dysfunction and dermatological abnormalities. TSC2 encodes tuberin, a putative GTPase activating protein for rap1 and rab5. The TSC1 gene was recently identified and codes for hamartin, a novel protein with no significant homology to tuberin or any other known vertebrate protein. Here, we show that hamartin and tuberin associate physically in vivo and that the interaction is mediated by predicted coiled-coil domains. Our data suggest that hamartin and tuberin function in the same complex rather than in separate pathways.
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PMID:Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. 958 Jun 71

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

The scaffolding protein WAVE-1 (Wiskott-Aldrich syndrome protein family member 1) directs signals from the GTPase Rac through the Arp2/3 complex to facilitate neuronal actin remodeling. The WAVE-associated GTPase activating protein called WRP is implicated in human mental retardation, and WAVE-1 knock-out mice have altered behavior. Neuronal time-lapse imaging, behavioral analyses, and electrophysiological recordings from genetically modified mice were used to show that WAVE-1 signaling complexes control aspects of neuronal morphogenesis and synaptic plasticity. Gene targeting experiments in mice demonstrate that WRP anchoring to WAVE-1 is a homeostatic mechanism that contributes to neuronal development and the fidelity of synaptic connectivity. This implies that signaling through WAVE-1 complexes is essential for neural plasticity and cognitive behavior.
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PMID:A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory. 1721 96

Mutations in regulators and effectors of the Rho GTPases underlie various forms of mental retardation (MR). Among them, oligophrenin-1 (OPHN1), which encodes a Rho-GTPase activating protein, was one of the first Rho-linked MR genes identified. Upon characterization of OPHN1 in hippocampal brain slices, we obtained evidence for the requirement of OPHN1 in dendritic spine morphogenesis and neuronal function of CA1 pyramidal neurons. Organotypic hippocampal brain slice cultures are commonly used as a model system to investigate the morphology and synaptic function of neurons, mainly because they allow for the long-term examination of neurons in a preparation where the gross cellular architecture of the hippocampus is retained. In addition, maintenance of the trisynaptic circuitry in hippocampal slices enables the study of synaptic connections. Today, a multitude of gene transfer methods for postmitotic neurons in brain slices are available to easily manipulate and scrutinize the involvement of signaling molecules, such as Rho GTPases, in specific cellular processes in this system. This chapter covers techniques detailing the preparation and culturing of organotypic hippocampal brain slices, as well as the production and injection of lentivirus into brain slices.
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PMID:Characterization of oligophrenin-1, a RhoGAP lost in patients affected with mental retardation: lentiviral injection in organotypic brain slice cultures. 1837 70

The OPHN1 gene encodes a Rho-GTPase activating protein (RhoGAP), and mutations in OPHN1 are responsible for non-specific X-linked mental retardation (NSMR). A SNP located in the 5'-untranslated region (UTRs) of OPHN1 (rs492933) was examined by PCR-RFLP to assess its contribution to cognitive ability in 234 unrelated healthy and MR children in the Qinba Mountain region in Shaanxi. The allelic frequencies of rs492933 were 0.826 for the C allele and 0.174 for the T allele. Genotype frequencies and allelic frequencies were not significantly different between the MR and the controls, or between the borderline group and the controls. In conclusion, there is no association between the OPHN1 gene polymorphism and NSMR in the Qinba Mountain region children.
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PMID:[Anassociation study between OPHN1 gene rs492933 polymorphism and mental retardation in children of the Qinba Mountain region.]. 1893 Aug 91