Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The study of the molecular pathogenesis of epilepsy in tuberous sclerosis has taken on a new dimension with the identification of the TSC1 and TSC2 genes. While the development of seizures is ultimately related to mutations in one of the two genes, the mechanism underlying the genotype-phenotype relationship remains a puzzle. This chapter, presented arguments in favor of the hypothesis that abnormal cortical excitability originates in and around focal areas of structural malformations (i.e., cortical tubers and dysplasia) and that these "lesions" are the biologic consequences of tuberin and/or hamartin dysfunction. This model relies on the concept of a multistep process occurring early in cortical development whereby certain progenitor cells in the germinal layer of the ventricular zone destined for the cortex undergo inactivation of the TSC1 or TSC2 locus (Fig. 2). Immature neuroepithelial cells carrying "two-hit" mutations at either locus are believed to proliferate, migrate, and differentiate abnormally, resulting in the formation of "dysplastic" cells that are heterotopic in distribution. The pathology of the classic tuber suggests a clonal expansion of the bizarre-appearing giant cells that display incomplete, multilineage, and often ambiguous phenotype. Further, they infiltrate the six-layered structure of the cortex to form a poorly circumscribed area containing a mixture of cell types to create a highly disorganized region of a neuronal and glial network. Whether arising from the dysplastic "two-hit" target cells themselves or adjacent "innocent" bystander neurons as a result of aberrant cell-cell interaction, abnormal epileptic discharges originate from these structural abnormalities. The mechanism of how TSC1 and TSC2 inactivation causes tuber to develop is not known, but emerging experimental evidence suggests a disruption of the hamartin-tuberin "haloenzyme" in the regulation of cell size and number via the insulin signaling pathway and a p27/CDK-dependent mechanism. Biochemically, TSC1/TSC2 may associate with cytoskeletal components and vesicular adaptors in regulating sorting and trafficking of newly synthesized and recycling proteins in the post-Golgi compartments. As such, spatial and temporal localization of proteins may be affected in tuberin or hamartin-deficient neuronal cells where proper synaptic delivery of neurotransmitters plays an important role in normal cerebral function. We are in the earliest stages of understanding the role of TSC genes in epileptogenesis. To test the hypothesis outlined earlier, there is a need to create in vitro and in vivo models, as direct human experimentation is not feasible. To date, there are several rodent models of TSC, both spontaneous and recombinant strains. Unfortunately, none has consistently developed spontaneous cortical tubers, although one example was reported in an otherwise asymptomatic Eker rat (Mizuguchi et al., 2000). If the "two-hit" hypothesis is operational in tubers, as seen in other TSC lesions, it follows that radiation and chemical carcinogens should have a quantitative and qualitative effect on the development of these cerebral malformations. In preliminary experiments, we have found evidence of areas of cortical dysplasia in Eker rats irradiated early in life (Fig. 3). These dysplastic [figure: see text] cells stained positively with NeuN, consistent with the immunophenotype of cells in tubers. Alternatively, one can analyze the in vivo and in vitro characteristics of neuroprogenitor cells that are deficient of hamartin or tuberin. While homozygous mutants of TSC1 and TSC2 are lethal during midgestation, one of several techniques can be used to derive mutant neuroepithelial cells, including the procurement of -/- cells prior to embryonic deaths and subsequent cortical transplantation into syngeneic animals, development of conditional "knock outs," or chimeric mutants. These approaches, with their unique advantages and disadvantages, will be helpful in gaining insights into the development of cortical tubers and their electrophysiologic consequences.
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PMID:Tuberous sclerosis as an underlying basis for infantile spasm. 1204 Aug 99

Focal cortical dysplasia (FCD) is characterized by a localized malformation of the neocortex and underlying white matter. Balloon cells, similar to those observed in tuberous sclerosis, are present in many cases (FCD(bc)). In these patients, a hyperintense funnel-shaped subcortical lesion tapering toward the lateral ventricle was the characteristic finding on fluid-attenuated inversion recovery magnetic resonance imaging scans. Surgical lesionectomy results in complete seizure relief. Although the pathogenesis of FCD(bc) remains uncertain, histopathological similarities indicate that FCD(bc) may be related pathogenetically to tuberous sclerosis. Here, we studied alterations of the TSC1 and TSC2 genes in a cohort of patients with chronic, focal epilepsy and histologically documented FCD(bc) (n = 48). DNA was obtained after microdissection and laser-assisted isolation of balloon cells, dysplastic neurons, and nonlesional cells from adjacent normal brain tissue. Sequence alterations resulting in amino acid exchange of the TSC1 gene product affecting exons 5 and 17 and silent base exchanges in exons 14 and 22 were increased in patients with FCD(bc) compared with 200 control individuals (exon 5, 2.3% FCD(bc) vs 0% C; exon 17, 35% FCD(bc) vs 1.0% C; exon 14, 37.8% FCD(bc) vs 15% C; exon 22, 45% FCD(bc) vs 23.8% C). Sequence alterations could be detected in FCD(bc) and in adjacent normal cells. In 24 patients, DNA was suitable to study loss of heterozygosity at the TSC1 gene locus in microdissected FCD(bc) samples compared with control tissue. Eleven FCD(bc) cases exhibited loss of heterozygosity. In the TSC2 gene, only silent polymorphisms were detected at similar frequencies as in controls. Our findings indicate that FCD(bc) constitutes a clinicopathological entity with distinct neuroradiological, neuropathological, and molecular genetic features. These data also suggest a role of the TSC1 gene in the development of FCD(bc) and point toward a pathogenic relationship between FCD(bc) and the tuberous sclerosis complex.
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PMID:Focal cortical dysplasia of Taylor's balloon cell type: mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis. 1211 41

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

We review here those malformations of the cerebral cortex which are most often observed in epilepsy patients, for which a genetic basis has been elucidated or is suspected and give indications for genetic testing. There are three forms of lissencephaly (agyria-pachygyria) resulting from mutations of known genes, which can be distinguished because of their distinctive imaging features. They account for about 85% of all licence-phalies. Lissencephaly with posteriorly predominant gyral abnormality is caused by mutations of the LIS1 gene on chromosome 17. Anteriorly predominant lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in heterozygous females are caused by mutations of the XLIS (or DCX) gene. Mutations of the coding region of XLIS were found in all reported pedigrees, and in most sporadic female patients with SBH. Missense mutations of both LIS1 and XLIS genes have been observed in some of the rare male patients with SBH. Autosomal recessive lissencephaly with cerebellar hypoplasia has been associated with mutations of the reelin gene. With few exceptions, children with lissencephaly have severe developmental delay and infantile spasms early in life. Patients with SBH have a mild to severe mental retardation with epilepsy of variable severity and type. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of typical BPNH with focal epilepsy in females and prenatal lethality in males. About 88% of patients have focal epilepsy. Filamin A (FLNA) mutations have been reported in some families and in sporadic patients. Additional, possibly autosomal recessive gene(s) are likely to be involved in causing BPNH non-linked to FLN1. Tuberous sclerosis (TS) is a dominant disorder caused by mutations in at lest two genes, TSC1 and TSC2. 75% of cases are sporadic. Most patients with TS have epilepsy. Infantile spasms are a frequent early manifestation of TS. Schizencephaly (cleft brain) has a wide anatomo-clinical spectrum, including focal epilepsy in most patients. Familial occurrence is rare. Heterozygous mutations in the EMX2 gene have been reported in some patients. However, at present, there is no clear indication on the possible pattern of inheritance and on the practical usefulness that mutation detection in an individual with schizencephaly would carry in terms of genetic counselling. Amongst several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria had familial occurrence on several occasions. Genetic heterogeneity is likely, including autosomal recessive, X-linked dominant, X-linked recessive inheritance and association to 22q11.2 deletions. FISH analysis for 22q11.2 is advisable in all patients with perisylvian polymicrogyria. Parents of an affected child with normal karyotype should be given up to a 25% recurrence risk.
Seizure 2002 Apr
PMID:Epileptogenic brain malformations: clinical presentation, malformative patterns and indications for genetic testing. 1218 71

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

Tuberous sclerosis (TS) is a genetic disorder affecting multiple body systems, and resulting from alterations in cell differentiation and proliferation. The disease is characterized by the development of benign hamartomatous tumors: neurofibromas and angiofibromas, located in the skin, central nervous system, mucosas and other organs. Abnormal neural cell migration plays an important role in the neurological dysfunctions found in TS, the predominant features being mental retardation, seizures and behavioral disorders. The condition is produced by mutations in genes TSC1 of chromosome 9q34 and TSC2 of chromosome 16p13.3, and exhibits a dominant autosomal hereditary trait--though 60-70% of cases are sporadic and represent new mutations. The phenotype is highly variable. The prevalence of TS varies between 1/6000 and 1/10,000 live births. The present study reports the case of a 21-year-old male with TS and oral manifestations of the disease. The clinical characteristics are described, along with the diagnostic criteria and the management strategies, with a review of the literature on the disease.
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PMID:Tuberous sclerosis: presentation of a clinical case with oral manifestations. 1261 72

Tuberous sclerosis complex (TSC) is a genetic disorder characterized by seizures, mental disability, renal dysfunction and dermatological abnormalities. The disease is caused by inactivation of either hamartin or tuberin, the products of the TSC1 and TSC2 tumour-suppressor genes. Hamartin and tuberin form a complex and antagonise phosphoinositide 3-kinase/protein kinase B/target of rapamycin signal transduction by inhibiting p70 S6 kinase, an activator of translation, and activating 4E-binding protein 1, an inhibitor of translation initiation. Phosphorylation-dependent binding between tuberin and members of the 14-3-3 protein family indicates how the tuberin-hamartin complex may interact with upstream and downstream effectors, and suggests how phosphorylation-dependent regulation of the complex may be controlled.
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PMID:Regulation of tuberous sclerosis complex (TSC) function by 14-3-3 proteins. 1277 61

Tuberous sclerosis complex is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, and benign tumors of the brain, skin, heart, and kidneys. Hamartin and tuberin, the products of the TSC1 and TSC2 genes, respectively, form a complex and inhibit signaling by the mammalian target of rapamycin. Here, we demonstrate that endogenous hamartin is threonine-phosphorylated during nocodazole-induced G2/M arrest and during the G2/M phase of a normal cell cycle. In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (Thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70S6 kinase by the hamartin-tuberin complex. These findings support a model in which phosphorylation of hamartin regulates the function of the hamartin-tuberin complex during the G2/M phase of the cell cycle.
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PMID:Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. 1455 Dec 5

Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder associated with mutations in TSC1, which codes for hamartin, or TSC2, which codes for tuberin. The brain is one of the most severely affected organs, and CNS lesions include cortical tubers and subependymal giant cell astrocytomas, resulting in mental retardation and seizures. Tuberin and hamartin function together as a complex in mammals and Drosophila. We report here the association of Pam, a protein identified as an interactor of Myc, with the tuberin-hamartin complex in the brain. The C terminus of Pam containing the RING zinc finger motif binds to tuberin. Pam is expressed in embryonic and adult brain as well as in cultured neurons. Pam has two forms in the rat CNS, an approximately 450-kDa form expressed in early embryonic stages and an approximately 350-kDa form observed in the postnatal period. In cortical neurons, Pam co-localizes with tuberin and hamartin in neurites and growth cones. Although Pam function(s) are yet to be defined, the highly conserved Pam homologs, HIW (Drosophila) and RPM-1 (Caenorhabditis elegans), are neuron-specific proteins that regulate synaptic growth. Here we show that HIW can genetically interact with the Tsc1.Tsc2 complex in Drosophila and could negatively regulate Tsc1.Tsc2 activity. Based on genetic studies, HIW has been implicated in ubiquitination, possibly functioning as an E3 ubiquitin ligase through the RING zinc finger domain. Therefore, we hypothesize that Pam, through its interaction with tuberin, could regulate the ubiquitination and proteasomal degradation of the tuberin-hamartin complex particularly in the CNS.
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PMID:Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. 1455 97


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