Evidence That the Gene for Tuberous Sclerosis Is on Chromosome 9

Fryer, Alan; Connor, J. M.; Povey, S.; Yates, John R.; Chalmers, A H; Fraser, I. S.; Yates, Alan D.; Osborne, J. P.

doi:10.1016/s0140-6736(87)90416-8

Cited by 362 publications

(104 citation statements)

References 20 publications

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“…For example, the human neurodevelopmental disorder TSC is characterized by epilepsy, autism spectrum disorder, and cognitive disability (37) and results from loss of function mutations in the TSC1 or TSC2 genes. The protein products of these genes form a complex that negatively regulates mTOR signaling, however the mechanisms by which changes in mTOR signaling lead to deregulated neural activity are not well understood (38)(39)(40). In mice, loss of Tsc1 leads to imbalances in synaptic excitation/inhibition, increased overall network activity, and seizures, which are a hallmark of this disorder (41).…”

Section: Resultsmentioning

confidence: 99%

Voltage-sensitive rhodol with enhanced two-photon brightness

Kulkarni

Kramer

Pourmandi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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We have designed, synthesized, and applied a rhodol-based chromophore to a molecular wire-based platform for voltage sensing to achieve fast, sensitive, and bright voltage sensing using twophoton (2P) illumination. Rhodol VoltageFluor-5 (RVF5) is a voltage-sensitive dye with improved 2P cross-section for use in thick tissue or brain samples. RVF5 features a dichlororhodol core with pyrrolidyl substitution at the nitrogen center. In mammalian cells under one-photon (1P) illumination, RVF5 demonstrates high voltage sensitivity (28% ΔF/F per 100 mV) and improved photostability relative to first-generation voltage sensors. This photostability enables multisite optical recordings from neurons lacking tuberous sclerosis complex 1, Tsc1, in a mouse model of genetic epilepsy. Using RVF5, we show that Tsc1 KO neurons exhibit increased activity relative to wild-type neurons and additionally show that the proportion of active neurons in the network increases with the loss of Tsc1. The high photostability and voltage sensitivity of RVF5 is recapitulated under 2P illumination. Finally, the ability to chemically tune the 2P absorption profile through the use of rhodol scaffolds affords the unique opportunity to image neuronal voltage changes in acutely prepared mouse brain slices using 2P illumination. Stimulation of the mouse hippocampus evoked spiking activity that was readily discerned with bath-applied RVF5, demonstrating the utility of RVF5 and molecular wire-based voltage sensors with 2P-optimized fluorophores for imaging voltage in intact brain tissue. Neuronal membrane potential dynamics drive neurotransmitter release and are therefore responsible for the unique physiology associated with neurons at cellular, circuit, and organismal levels. Despite the central importance of proper neuronal firing to human health, an integrated understanding of neuronal activity in the context of larger brain circuits remains elusive, due in part to a lack of methods for interrogating membrane potential dynamics with sufficient spatial and temporal resolution.Traditional methods for monitoring membrane potential rely heavily on the use of invasive electrodes, through one of two methods. The first method, patch-clamp electrophysiology, uses a single electrode to make contact with or puncture a cell to record changes in membrane potential, sacrificing throughput and spatial resolution to achieve a comprehensive description of a single cellular electrophysiological profile. A second method uses multielectrode arrays (MEAs), in which patterned arrays of electrodes introduced to cells or tissues report on electrical changes. Spatial resolution of MEAs depends on the number and positioning of the electrodes within the array. Although throughput is improved relative to patch-clamp electrophysiology, the extracellularly recorded signals are typically less sensitive than whole-cell methods and can be an amalgamation of several cells, making deconvolution of recorded signals and precise correlation to specific cells difficult or impossible. Addi...

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Section: Resultsmentioning

confidence: 99%

Voltage-sensitive rhodol with enhanced two-photon brightness

Kulkarni

Kramer

Pourmandi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…13 Further genetic analyses revealed the gene with 23 exons and an 8.6 kb mRNA transcript. Protein product hamartin (TSC1) is a 1164-amino-acid/130 kDa protein expressed in most human tissues, including the brain, kidney, heart, liver, small and large intestine, prostate or testes (Fig.…”

Section: Hamartinmentioning

confidence: 99%

Hamartin and tuberin: Working together for tumour suppression

Jóźwiak

2005

Intl Journal of Cancer

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TSC1 and TSC2 are two recently identified tumour suppressor genes encoding hamartin and tuberin, respectively, and involved in pathogenesis of tuberous sclerosis, neurological disorder connected with the development of hamartomas in numerous organ systems, including the brain, kidneys, heart and liver. Both protein products of TSC1 and TSC2 form an intracellular complex exerting GTPase-activating (GAP) activity towards a small G protein, Ras homologue enriched in brain (Rheb). Inhibition of Rheb is important for the regulation of mTOR pathway, while mutation of hamartin or tuberin results in uncontrolled cell cycle progression. Tuberin, possessing the Rheb-GAP domain, is phosphorylated by several kinases that confer the signals of growth factor stimulation or low cellular energy levels. Such a modification of tuberin influences its activity within the complex with hamartin and positively or negatively modulates mTOR-regulated protein translation and cellular proliferation. Current article describes biochemical properties of hamartin and tuberin, their known regulatory phosphorylation sites and binding partners. ' 2005 Wiley-Liss, Inc.

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“…Two tumor suppressing genes, TSC1 and TSC2, are though to be responsible for the pathogenesis of TS and are located on chromosomes 9q and 16p, respectively (Fryer et al, 1987). About two thirds of cases are new mutations in patients with no family history of this disorder.…”

Section: Introductionmentioning

confidence: 99%

Tuberous Sclerosis: A Case Report with Oral Manifestation

Curi¹,

Cardoso²,

Ikuta³

et al. 2014

Int. J. Odontostomat.

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ABSTRACT:Tuberous sclerosis is an autosomal dominant neurocutaneous syndrome, which may involve multiple organ systems and shows highly variable clinical manifestations. Oral manifestations, including lesions on hard tissues, enamel hypoplasia and gingival hyperplasia have been previously described. We report a case of 25-year-old woman with this syndrome presenting multiple fibrous nodules on the buccal mucosa and lips. Awareness of the different oral manifestations of tuberous sclerosis is important to ensure appropriate diagnosis and treatment.

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Evidence That the Gene for Tuberous Sclerosis Is on Chromosome 9

Cited by 362 publications

References 20 publications

Voltage-sensitive rhodol with enhanced two-photon brightness

Voltage-sensitive rhodol with enhanced two-photon brightness

Hamartin and tuberin: Working together for tumour suppression

Tuberous Sclerosis: A Case Report with Oral Manifestation

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