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)

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by epilepsy, mental retardation and hamartomatous lesions in multiple organs. It has been shown that the genes responsible for TSC, TSC1 and TSC2, act as tumor suppressors, but the mechanism of hamartomatous growth in several tissues is not completely understood. The TSC hamartomas are essentially benign and they rarely progress to malignant tumors. In this report, we cultured the angiofibroma stroma cells of three adult TSC patients and compared these cells with normal skin fibroblasts for their proliferative capacity, cell morphology and mitotic cycle using a stain for microtubules and the expression of the senescent associated beta-galactosidase (SA beta-Gal). Cultured angiofibroma stroma cells from TSC patients displayed several characteristics observed in human senescent fibroblasts; a low proliferative capacity, an increase in cell size, increased binucleated cells in association with abnormal cytokinesis and increased SA beta-Gal positives. Growth of facial angiofibromas in TSC may be caused by a gain in enhanced sensitivity toward some of the potential mitogens and forced multiplication without loss of the cellular senescent program; this may be the reason why TSC hamartomas rarely progress to malignancy and why the growths are limited to a finite size.
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PMID:Cellular senescence of angiofibroma stroma cells from patients with tuberous sclerosis. 1037 5

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction and dermatological abnormalities. Mutations to either the TSC1 or TSC2 gene are responsible for the disease. The TSC1 gene encodes hamartin, a 130-kDa protein without significant homology to other known mammalian proteins. Analysis of the amino acid sequence of tuberin, the 200-kDa product of the TSC2 gene, identified a region with limited homology to GTPase-activating proteins. Previously, we demonstrated direct binding between tuberin and hamartin. Here we investigate this interaction in more detail. We show that the complex is predominantly cytosolic and may contain additional, as yet uncharacterized components alongside tuberin and hamartin. Furthermore, because oligomerization of the hamartin carboxyl-terminal coiled coil domain was inhibited by the presence of tuberin, we propose that tuberin acts as a chaperone, preventing hamartin self-aggregation.
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PMID:Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin. 1058 43

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disorder limited almost exclusively to women of reproductive age. LAM affects about 5% of women with tuberous sclerosis complex (TSC). LAM also occurs in women who do not have TSC (sporadic LAM). TSC is a tumour suppressor gene syndrome characterised by seizures, mental retardation, and tumours in the brain, heart, and kidney. Angiomyolipomas, which are benign tumours with smooth muscle, fat, and dysplastic vascular components, are the most common renal tumour in TSC. Renal angiomyolipomas also occur in 63% of sporadic LAM patients. We recently found that 54% of these angiomyolipomas have TSC2 loss of heterozygosity, leading to the hypothesis that sporadic LAM is genetically related to TSC. In this study, we screened DNA from 21 women with sporadic LAM for mutations in all 41 exons of TSC2. Twelve of the patients had known renal angiomyolipomas. No TSC2 mutations were detected. We did find three silent TSC2 polymorphisms. We conclude that patients with sporadic LAM, including those with renal angiomyolipomas, do not have a high frequency of germline mutations in the coding region of TSC2.
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PMID:Mutational analysis of the tuberous sclerosis gene TSC2 in patients with pulmonary lymphangioleiomyomatosis. 1063 37

Tuberous sclerosis complex (TSC) is a common genetic disorder in which affected individuals can develop mental retardation, developmental brain defects, and seizures. Two genetic loci are responsible for TSC: TSC1 on chromosome 9q and TSC2 on chromosome 16p. Here, we report our analysis of TSC1 (hamartin) and TSC2 (tuberin) protein expression in the central nervous system (CNS). Both tuberin and hamartin are expressed in neurons and astrocytes where they physically interact. In the mouse cerebellum in vivo, tuberin predominantly localizes to the perinuclear region of the Purkinje cell, whereas hamartin is distributed along neuronal or astrocytic processes. In contrast, both hamartin and tuberin demonstrate similar neuronal expression patterns in pure neuronal cultures in vitro. Additionally, hamartin is highly expressed in astrocytes in mixed neuron-glia cultures in vitro, suggesting that hamartin may be important for astrocyte growth control. Unlike tuberin, loss of hamartin expression was not observed in sporadic astrocytomas. These results suggest that tuberin and hamartin may differentially contribute to the CNS pathology in TSC.
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PMID:Expression of the tuberous sclerosis complex gene products, hamartin and tuberin, in central nervous system tissues. 1066 63

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction and dermatological abnormalities. Inactivating mutations to either of the TSC1 and TSC2 tumour suppressor genes are responsible for the disease. TSC1 and TSC2 encode two large novel proteins called hamartin and tuberin, respectively. Hamartin and tuberin interact directly with each other and it has been reported that tuberin may act as a chaperone, preventing hamartin self-aggregation and maintaining the tuberin-hamartin complex in a soluble form. In this study, the ability of tuberin to act as a chaperone for hamartin was used to investigate the tuberin-hamartin interaction in more detail. A domain within tuberin necessary for the chaperone function was identified, and the effects of TSC2 missense mutations on the tuberin-hamartin interaction were investigated to allow specific residues within the central domain of tuberin that are important for the interaction with hamartin to be pin-pointed. In addition, the results confirm that phosphorylation may play an important role in the formation of the tuberin-hamartin complex. Although mutations that prevent tuberin tyrosine phosphorylation also inhibit tuberin-hamartin binding and the chaperone function, our results indicate that only hamartin is phosphorylated in the tuberin-hamartin complex.
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PMID:TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex. 1174 32

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by seizures, mental retardation, autism, and tumors of multiple organs. Renal disease in TSC includes angiomyolipomas, cysts, and renal cell carcinomas. It is known that somatic mutations in the von Hippel Lindau (VHL) tumor suppressor gene occur in most clear cell renal carcinomas. To determine whether TSC-associated clear cell carcinomas also contain VHL mutations, we analyzed six tumors for loss of heterozygosity in the VHL gene region of chromosome 3p and for mutations in the VHL gene. Four of the patients were women between the ages of 34 and 68 years, and two were males under the age of 21 years. The loss of heterozygosity analysis was performed using polymorphic microsatellite markers, and the mutational analysis was performed using direct sequencing. Chromosome 3p loss of heterozygosity was not detected, and no VHL mutations were identified. These findings suggest that mutations in the TSC1 and TSC2 genes lead to clear cell renal carcinogenesis via an alternate pathway not involving VHL mutations.
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PMID:Mutational analysis of the von hippel lindau gene in clear cell renal carcinomas from tuberous sclerosis complex patients. 1190 37

This review will consider patterns of developmental neuropathologic abnormalities-malformations of cortical development (MCD)--encountered in infants (often with infantile spasms), children, and adults with intractable epilepsy. Treatment of epilepsy associated with some MCD, such as focal cortical dysplasia and tubers of tuberous sclerosis, may include cortical resection performed to remove the "dysplastic" region of cortex. In extreme situations (eg, hemimegalencephaly), hemispherectomy may be carried out on selected patients. Neuropathologic (including immunohistochemical) findings within these lesions will be considered. Other conditions that cause intractable epilepsy and often mental retardation, yet are not necessarily amenable to surgical treatment (eg, lissencephaly, periventricular nodular heterotopia, double cortex syndrome) will be discussed. Over the past 10 years there has been an explosion of information on the genetics of MCD. The genes responsible for many MCD (eg, TSC1, TSC2, LIS-1, DCX, FLN1) have been cloned and permit important mechanistic studies to be carried out with the purpose of understanding how mutations within these genes result in abnormal cortical cytoarchitecture and anomalous neuroglial differentiation. Finally, novel techniques allowing for analysis of patterns of gene expression within single cells, including neurons, is likely to provide answers to the most vexing and important question about these lesions: Why are they epileptogenic?
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PMID:Neurodevelopmental disorders as a cause of seizures: neuropathologic, genetic, and mechanistic considerations. 1195 76

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor predisposition syndrome characterized by benign proliferations (hamartomas). In the brain, individuals with TSC develop autism, mental retardation and seizures associated with focal cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). We hypothesize that dysregulated astrocyte function due to mutations in the tumor suppressor genes, TSC1 and TSC2, may contribute to the pathogenesis of these brain abnormalities. In this report, we demonstrate that mice heterozygous for a targeted defect in either the Tsc1 or Tsc2 genes(Tsc1+/- and Tsc2+/- mice) exhibit a 1.5-fold increase in the number of astrocytes in vivo. Whereas increased astrocyte numbers in vivo were suggestive of a proliferative advantage, Tsc2+/- primary astrocyte cultures did not show a cell-autonomous growth advantage, anchorage-independent growth, increased saturation density, or increased fluid-phase endocytosis compared to wild type astrocytes. Tsc2 null mouse embryonic fibroblasts (MEFs) however, did exhibit increased saturation density compared to Tsc2 wild type controls. In both Tsc2+/- astrocytes and Tsc2 null mouse embryonic fibroblasts, p27-Kip1 expression was decreased compared to wild type cells, and was reversed by tuberin re-expression in Tsc2-/- MEFs. In contrast, no change in endocytosis was observed upon tuberin re-expression in Tsc2-/- MEFs. Collectively, these results suggest Tsc heterozygosity may provide a non-cell-autonomous growth advantage for astrocytes that may involve p27-Kip1 expression.
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PMID:Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2+/- cells. 1203 87

Tuberous sclerosis is caused by mutations to either the TSC1 or TSC2 tumor suppressor gene. The disease is characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction, and dermatological abnormalities. TSC1 encodes a 130-kDa protein called hamartin, and TSC2 encodes a 200-kDa protein called tuberin. Although it has been shown that hamartin and tuberin form a complex and mediate phosphoinositide 3-kinase/Akt-dependent phosphorylation of the ribosomal protein S6, it is not yet clear how inactivation of either protein leads to tuberous sclerosis. Therefore, to obtain additional insight into tuberin and hamartin function, yeast two-hybrid screening experiments were performed to identify proteins that interact with tuberin. One of the proteins identified was 14-3-3zeta, a member of the 14-3-3 protein family. The interaction between tuberin and 14-3-3zeta was confirmed in vitro and by co-immunoprecipitation; multiple sites within tuberin for 14-3-3zeta binding were identified; and it was determined that 14-3-3zeta associated with the tuberin-hamartin complex. Finally, it was shown that the tuberin/14-3-3zeta interaction is regulated by Akt-mediated phosphorylation of tuberin, providing insight into how tuberin may regulate phosphorylation of S6.
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PMID:Identification and characterization of the interaction between tuberin and 14-3-3zeta. 1217 84

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome characterized by seizures, mental retardation, autism, and tumors of the brain, kidney, heart, retina, and skin. TSC is caused by mutations in either TSC1 or TSC2, both of which are tumor suppressor genes. Hamartin, the protein product of TSC1, was found to interact with the ezrin-radixin-moesin family of cytoskeletal proteins and to activate the small GTPase Rho. To determine whether tuberin, the TSC2 product, can also activate Rho, we stably expressed full-length human tuberin in two cell types: MDCK cells and ELT3 cells. ELT3 cells lack endogenous tuberin expression. We found that expression of human tuberin in both MDCK and ELT3 cells was associated with an increase in the amount of Rho-GTP, but not in Rac1-GTP or cdc42-GTP. Tuberin expression increased cell adhesion in both cell types, and decreased chemotactic cell migration in ELT3 cells. In MDCK cells, there was a decrease in the amount of total Focal Adhesion Kinase (FAK) and an increase in the fraction of phosphorylated FAK. These findings demonstrate for the first time that tuberin activates Rho and regulates cell adhesion and migration. Pathways involving Rho activation may have relevance to the clinical manifestations of TSC, including pulmonary lymphangioleiomyomatosis.
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PMID:Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration. 1246 66


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