Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 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 a multiorgan genetic disease caused by inactivation of either the TSC1 or TSC2 genes. The disorder typically has profound neurologic involvement and often presents early in life with epilepsy, developmental delay, mental retardation, and autism. These features are generally accepted to result from structural brain abnormalities that are found in patients with TSC. Although much progress has recently been made in discerning the function(s) of the TSC genes, many questions remain as to the role of these genes in brain development and homeostasis. This review will summarize recent progress and suggest future avenues of basic science research.
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PMID:The neurobiology of tuberous sclerosis complex. 1681 74

Tuberous sclerosis complex (TSC) is a multisystem disorder that affects numerous organ systems. Brain lesions that form during development, known as tubers, are highly associated with epilepsy, cognitive disability, and autism. Following the identification of two genes and their encoded proteins, TSC1 (hamartin) and TSC2 (tuberin), responsible for TSC, identification of several downstream protein cascades that might be affected in TSC have been discovered. Of primary importance is the mammalian target of rapamycin pathway that controls cell growth and protein synthesis. The mechanisms governing brain lesion growth have not been fully identified but likely altered regulation of the mammalian target of rapamycin cascade by hamartin and tuberin during development leads to aberrant cell growth. Secondary effects of TSC gene mutations might disrupt normal neuronal migration and cerebral cortical lamination. Numerous studies have identified changes in gene and protein expression in animal models of TSC and in human TSC brain specimens that contribute to altered brain cytoarchitecture. This review will provide an overview of the neurobiological aspects of TSC.
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PMID:The neurobiology of the tuberous sclerosis complex. 1702 74

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 (TSC) is a hamartoma syndrome attributable to mutations in either TSC1 or TSC2 in which brain involvement causes epilepsy, mental retardation, and autism. We have reported recently (Meikle et al., 2007) a mouse neuronal model of TSC in which Tsc1 is ablated in most neurons during cortical development. We have tested rapamycin and RAD001 [40-O-(2-hydroxyethyl)-rapamycin], both mammalian target of rapamycin mTORC1 inhibitors, as potential therapeutic agents in this model. Median survival is improved from 33 d to more than 100 d; behavior, phenotype, and weight gain are all also markedly improved. There is brain penetration of both drugs, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream target of mTORC1. In addition, there is restoration of phospho-Akt and phospho-glycogen synthase kinase 3 levels in the treated mice, consistent with restoration of Akt function. Neurofilament abnormalities, myelination, and cell enlargement are all improved by the treatment. However, dysplastic neuronal features persist, and there are only modest changes in dendritic spine density and length. Strikingly, mice treated with rapamycin or RAD001 for 23 d only (postnatal days 7-30) displayed a persistent improvement in phenotype, with median survival of 78 d. In summary, rapamycin/RAD001 are highly effective therapies for this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 and Akt signaling and, consequently, cell size and myelination. Although caution is appropriate, the results suggest the possibility that rapamycin/RAD001 may have benefit in the treatment of TSC brain disease, including infantile spasms.
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PMID:Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. 1912 12

Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.
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PMID:Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. 1856 33

Axon formation is fundamental for brain development and function. TSC1 and TSC2 are two genes, mutations in which cause tuberous sclerosis complex (TSC), a disease characterized by tumor predisposition and neurological abnormalities including epilepsy, mental retardation, and autism. Here we show that Tsc1 and Tsc2 have critical functions in mammalian axon formation and growth. Overexpression of Tsc1/Tsc2 suppresses axon formation, whereas a lack of Tsc1 or Tsc2 function induces ectopic axons in vitro and in the mouse brain. Tsc2 is phosphorylated and inhibited in the axon but not dendrites. Inactivation of Tsc1/Tsc2 promotes axonal growth, at least in part, via up-regulation of neuronal polarity SAD kinase, which is also elevated in cortical tubers of a TSC patient. Our results reveal key roles of TSC1/TSC2 in neuronal polarity, suggest a common pathway regulating polarization/growth in neurons and cell size in other tissues, and have implications for the understanding of the pathogenesis of TSC and associated neurological disorders and for axonal regeneration.
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PMID:Tuberous sclerosis complex proteins control axon formation. 1879 42

Tuberous sclerosis complex (TSC) is a neurogenetic disorder caused by loss-of-function mutations in either the TSC1 or TSC2 genes and frequently results in prominent CNS manifestations, including epilepsy, mental retardation, and autism spectrum disorder. The TSC1/TSC2 protein complex plays a major role in controlling the Ser/Thr kinase mammalian target of rapamycin (mTOR), which is a master regulator of protein synthesis and cell growth. In this study, we show that endoplasmic reticulum (ER) stress regulates TSC1/TSC2 complex to limit mTOR activity. In addition, Tsc2-deficient rat hippocampal neurons and brain lysates from a Tsc1-deficient mouse model demonstrate both elevated ER and oxidative stress. In Tsc2-deficient neurons, the expression of stress markers such as CHOP and HO-1 is increased, and this increase is completely reversed by the mTOR inhibitor rapamycin both in vitro and in vivo. Neurons lacking a functional TSC1/TSC2 complex have increased vulnerability to ER stress-induced cell death via the activation of the mitochondrial death pathway. Importantly, knockdown of CHOP reduces oxidative stress and apoptosis in Tsc2-deficient neurons. These observations indicate that ER stress modulates mTOR activity through the TSC protein complex and that ER stress is elevated in cells lacking this complex. They also suggest that some of the neuronal dysfunction and neurocognitive deficits seen in TSC patients may be attributable to ER and oxidative stress and therefore potentially responsive to agents moderating these pathways.
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PMID:Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner. 1942 Feb 59


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