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)

The genes, TSC1 on chromosome 9q34, encoding hamartin, and TSC2 on chromosome 16p13.3, encoding tuberin, are responsible for tuberous sclerosis (TSC). TSC is an autosomal dominant tumor suppressor gene syndrome affecting about 1 in 6000 individuals. It is characterized by mental retardation and epilepsy. A variety of tumors characteristically occur in different organs of TSC patients and are believed to result from defects in cell cycle/cell size control. Hamartin and tuberin form a complex providing a tentative explanation for the similar disease phenotype in TSC patients with mutations in either of these genes. Beside overlap in many features of patients with TSC1 and TSC2 mutations, data accumulated providing evidence for specific clinical differences. In this study, we performed a proteomic approach of two-dimensional gel electrophoresis with subsequent mass spectrometrical identification of protein spots after ectopic overexpression of human TSC1 or TSC2. We found the protein levels of the calumenin precursor; the complement component 1; heterogeneous nuclear ribonucleoproteins, C1/C2; heterogeneous nuclear ribonucleoprotein, C1-like protein; nascent polypeptide-associated complex-alpha; proteasome subunit alpha type 5; reticulocalbin 1 precursor; translationally-controlled tumor protein; UV excision repair protein, RAD23 homolog B; elongation factor 1-delta; and the eukaryotic initiation factors, eIF-4A-like NUK-34 and eIF-6; to be deregulated upon ectopic TSC gene expression. These findings suggest that deregulation of the control of these new target proteins might contribute to the development of tubers/hamartomas in tuberous sclerosis patients. The data are presented and discussed in the context of the published literature on proteomic approaches for the identification of targets of the TSC genes.
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PMID:The cellular response to ectopic overexpression of the tuberous sclerosis genes, TSC1 and TSC2: a proteomic approach. 1607 35

Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome affecting about 1 in 6000 individuals. It is characterized by mental retardation and epilepsy. A variety of tumors characteristically occur in different organs of TSC patients. The genes, TSC1 on chromosome 9q34, encoding hamartin, and TSC2 on chromosome 16p13.3, encoding tuberin are responsible for TSC. Hamartin and tuberin form a complex providing a tentative explanation for the similar disease phenotype in TSC patients with mutations in either of these genes. Besides overlap in many features of patients with TSC1 and TSC2 mutations, data accumulated provide evidence for specific clinical differences. Here, we performed microarray analyses of the gene expression response to overexpressed TSC1 or TSC2 in HeLa cells. Out of 2400 analysed genes we found 115 genes to be up-regulated > or =2-fold upon ectopic TSC1 overexpression and 284 genes to be up-regulated > or =2-fold via TSC2. Only 34 of these genes were up-regulated by both, TSC1 and TSC2. Whereas only 7 genes were down-regulated > or =2-fold via TSC1, ectopic TSC2 triggered a > or =2-fold down-regulation of 113 genes. Only 3 of these genes were down-regulated by TSC1 and TSC2. This study provides new insights into the cellular roles of TSC proteins and promotes discussion on whether separable functions of these proteins might be associated with the clinical differences of TSC1- and TSC2-associated disease.
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PMID:The tuberous sclerosis genes, TSC1 and TSC2, trigger different gene expression responses. 1621 Dec 38

Tuberous sclerosis complex (TSC) is a common genetic disorder in which affected individuals develop mental retardation, developmental brain defects and seizures. The TSC gene products, hamartin and tuberin, form a complex, of which tuberin is assumed to be the functional component being involved in a wide variety of different cellular processes. Here we report that tuberin protein levels are decreased in the frontal cortex of patients with Alzheimer's disease. In addition, tuberin levels are also decreased in Down syndrome brain samples positive for beta-amyloid plaques and neurofibrillary tangles. Analysis of NeuN revealed that this regulation is not a consequence of differences in the amount of postmitotic neurons. This first connection of tuberin to another common disease beside TSC stimulates new approaches to investigate the molecular development and to establish new therapeutic strategies.
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PMID:Tuberin--a new molecular target in Alzheimer's disease? 1634 38

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, autism, and tumors in the brain, retina, kidney, heart, and skin. The products of the TSC1 and TSC2 genes, hamartin and tuberin, respectively, heterodimerize and inhibit the mammalian target of rapamycin (mTOR). This review focuses on the genetic and biochemical basis of the renal and pulmonary manifestations of TSC, angiomyolipomas, and lymphangiomyomatosis, respectively. Genetic analyses of sporadic angiomyolipomas revealed that all three components (smooth muscle, vessels, and fat) derive from a common progenitor cell, indicating the ability of cells lacking tuberin to differentiate into multiple lineages. Other genetic studies showed that the benign smooth muscle cells of pulmonary lymphangiomyomatosis have the ability to migrate to other organs. These findings suggest that tuberin and hamartin play a role in the regulation of cellular migration and differentiation. We have found that tuberin activates B-Raf kinase and p42/44 MAPK and that cells lacking tuberin have low levels of B-Raf activity. We hypothesize that aberrant B-Raf activity in angiomyolipomas leads to abnormal cellular differentiation and migration.
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PMID:The role of tuberin in cellular differentiation: are B-Raf and MAPK involved? 1638 52

Mutations in one of two genes, TSC1 and TSC2, result in a similar disease phenotype by disrupting the normal interaction of their protein products, hamartin and tuberin, which form a functional signaling complex. Disruption of these genes in the brain results in abnormal cellular differentiation, migration, and proliferation, giving rise to the characteristic brain lesions of tuberous sclerosis complex (TSC) called cortical tubers. The most devastating complications of TSC affect the central nervous system and include epilepsy, mental retardation, autism, and glial tumors. Relevant animal models, including conventional and conditional knockout mice, are valuable tools for studying the normal functions of tuberin and hamartin and the way in which disruption of their expression gives rise to the variety of clinical features that characterize TSC. In the future, these animals will be invaluable preclinical models for the development of highly specific and efficacious treatments for children affected with TSC.
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PMID:Tuberous sclerosis complex: molecular pathogenesis and animal models. 1688 89

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction and dermatological abnormalities. TSC is caused by mutations affecting either of the tumor-suppressor genes TSC1 and TSC2. At least 495 mutations of TSC1 and TSC2 have been reported. Twenty-two males and 22 females who were diagnosed with TSC at the Seoul National University Children's Hospital between 1982 and 2002 were enrolled in the study. Forty-four patients were from different families and included nine familial cases and 35 sporadic cases. Denaturing high performance liquid chromatography and DNA sequencing analysis of TSC1 and TSC2 revealed 13 types of mutations (30%). One novel mutation of TSC1 and nine novel mutations of TSC2 were identified. The TSC1 mutation and one of the nine TSC2 mutations were missense mutations and seven of the nine TSC2 mutations caused truncation of proteins. One novel single nucleotide substitution was identified at the consensus splicing donor site of exon 39 (c.5,069-1G>A). This mutation is predicted to cause a splicing error. Of the TSC2 mutation loci, the correlation with cardiac rhabdomyoma was more significant when the mutation was in the C-terminal part of tuberin than the N-terminal part. This is the first extensive mutational analysis of TSC1 and TSC2 in Korean TSC patients.
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PMID:Mutational analysis of TSC1 and TSC2 in Korean patients with tuberous sclerosis complex. 1655 33

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor syndrome that affects approximately 1 in 6000 individuals. It is characterized by the development of tumors, named hamartomas, in the kidneys, heart, skin and brain. The latter often cause seizures, mental retardation, and a variety of developmental disorders, including autism. This disease is caused by mutations within the tumor suppressor gene TSC1 on chromosome 9q34 encoding hamartin or within TSC2 on chromosome 16p13.3 encoding tuberin. TSC patients carry a mutant TSC1 or TSC2 gene in each of their somatic cells, and loss of heterozygosity has been documented in a wide variety of TSC tumors. Recent data suggest that functional inactivation of TSC proteins might also be involved in the development of other diseases not associated with TSC, such as sporadic bladder cancer, breast cancer, ovarian carcinoma, gall bladder carcinoma, non-small-cell carcinoma of the lung, and Alzheimer's disease. Tuberin and hamartin form a heterodimer, suggesting they might affect the same processes. Tuberin is assumed to be the functional component of the complex and has been implicated in the regulation of different cellular functions. The TSC proteins regulate cell size control due to their involvement in the insulin signalling pathway. Furthermore, they are potent positive regulators of the cyclin-dependent kinase inhibitor p27, a major regulator of the mammalian cell cycle. Here we review the current knowledge on how mutations within the TSC genes could trigger deregulation of stability and localization of the tumor suppressor p27.
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PMID:The tuberous sclerosis genes and regulation of the cyclin-dependent kinase inhibitor p27. 1671 32

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disorder characterized by benign tumors (hamartomas) in various organs. The brain is one of the most severely affected organs with neuropsychiatric disorders including epilepsy, mental retardation and autism. The identification of TSC genes (TSC1 and TSC2) and their gene products (hamartin and tuberin, respectively), revealed that they function together as a complex. However, mutations in TSC2 are often accompanied by more severe neurologic deficits. Here, we show that hamartin and tuberin play different roles in NGF-treated cultured neuronal cells PC12h. The level of hamartin in PC12h cells was slightly and gradually increased, while those of tuberin rapidly increased upon NGF-induced neuronal differentiation in PC12h cells. Antisense for TSC1 (TSC1-AS) or TSC2-AS reduced expression of hamartin or tuberin, respectively, and enhanced S-phase of cell cycle in PC12h cells. Suppression of hamartin significantly enhanced neurite outgrowth after NGF-treatment in PC12h cells, while suppression of tuberin inhibited neurite outgrowth. Expression of activated V14RhoA reverted TSC1-AS induced abnormal neurite development. These results suggest that loss of hamartin results in abnormal neurite elongation through Rho inactivation in NGF-treated PC12h cells, which may be associated with the neurological manifestations of TSC.
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PMID:Antisense suppression of TSC1 gene product, hamartin, enhances neurite outgrowth in NGF-treated PC12h cells. 1737 23

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of multiple hamartomas distributed throughout the body, skin, brain, eyes, heart, kidney and lung. The affected genes are TSC1 and TSC2, encoding hamartin and tuberin respectively. The hamartin-tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation. The most common neurological manifestations of TSC are epilepsy, mental retardation, and autistic behavior. Epilespsy usually occurs during childhood and they need anticonvulsant medications through their life. In adulthood, multiple hamartomas is distributed in the kidney and lung. Individuals with lesions more than 4 cm in diameter or with extensive renal involvement should be referred to a nephrologist or urologist. Understanding variable phenotype expression improve management of TSC.
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PMID:[Care continuity for patients with tuberous sclerosis complex (TSC) during transition from childhood to adulthood]. 2007 6

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in humans characterized by the development of hamartomas in several organs, including renal angiomyolipomas, cardiac rhabdomyomas and subependymal giant cell astrocytomas. TSC causes disabling neurologic disorders, including epilepsy, mental retardation and autism. Brain lesions, including subependymal and subcortical hamartomas, have also been reported in TSC patients. TSC is associated with hamartomas and renal cell carcinoma (RCC) as well as sporadic tumors in TSC patient. Renal angiomyolipomas associated with TSC tend to be larger, bilateral, multifocal and present at a younger age compared with sporadic forms. Tuberous sclerosis complex of 2 genes, TSC2 encodes a protein called tuberin that normally exists in an active state and forms a heterodimeric complex with hamartin, the protein encoded by the TSC1. Deficiency ofTSC2 in Eker rat is associated with the development of tumors in several organs including kidney. The majority of renal cell tumors observed in the Eker rat originates from renal proximal tubules and are histologically similar to renal cell carcinoma in humans. On the other hand, mutations in DNA repair enzyme 8-oxoG-DNA glycosylase (OGG1) are associated with cancer. OGG1 gene is found somatically mutated in some cancer cells and is highly polymorphic among human cancers. Moreover, knockout mice in OGG1 developed spontaneously adenoma and carcinoma. We recently show that the constitutive expression of OGG1 in heterozygous (TSC2+/-) Eker rat and in angiomyolipomas kidney tissue from human is 2-3fold less than in kidney from wild-type rats and control human subjects. In addition, we show that loss of TSC2 in kidney tumor of Eker rat is associated with loss of OGG1 and accumulation significant levels of oxidative DNA damage 8-oxo-deoxyguanine suggesting that TSC2 and OGG1 play a major role in renal tumorigenesis.
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PMID:Tuberous sclerosis complex and DNA repair. 2068 97


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