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https://www.readbyqxmd.com/read/28211972/tsc2-c-1864c-t-variant-associated-with-mild-cases-of-tuberous-sclerosis-complex
#1
Laura S Farach, William T Gibson, Steven P Sparagana, Mark Nellist, Connie T R M Stumpel, Marja Hietala, Elliott Friedman, Deborah A Pearson, Susan P Creighton, Annemiek Wagemans, Reveel Segel, Efrat Ben-Shalom, Kit Sing Au, Hope Northrup
Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder with variable expressivity associated with hamartomatous tumors, abnormalities of the skin, and neurologic problems including seizures, intellectual disability, and autism. TSC is caused by pathogenic variants in either TSC1 or TSC2. In general, TSC2 pathogenic variants are associated with a more severe phenotype than TSC1 pathogenic variants. Here, we report a pathogenic TSC2 variant, c.1864C>T, p.(Arg622Trp), associated with a mild phenotype, with most carriers meeting fewer than two major clinical diagnostic criteria for TSC...
March 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28183733/neuronal-ctgf-ccn2-negatively-regulates-myelination-in-a-mouse-model-of-tuberous-sclerosis-complex
#2
Ebru Ercan, Juliette M Han, Alessia Di Nardo, Kellen Winden, Min-Joon Han, Leonie Hoyo, Afshin Saffari, Andrew Leask, Daniel H Geschwind, Mustafa Sahin
Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking neuronal Tsc1 have a hypomyelination phenotype. However, the mechanisms that underlie these phenotypes remain unknown. In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturation through the regulated secretion of connective tissue growth factor (CTGF)...
February 9, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28178598/novel-tsc1-and-tsc2-gene-mutations-in-chinese-patients-with-tuberous-sclerosis-complex
#3
Tingting Yu, Yingzhong He, Niu Li, Yunqing Zhou, Zhiping Wang, Qihua Fu, Jiwen Wang, Jian Wang
OBJECTIVE: The study was designed to identify pathogenic TSC1 or TSC2 gene mutations and provide solid evidence for the diagnosis of tuberous sclerosis complex (TSC). METHODS: 11 unrelated Chinese patients with TSC were investigated in the present study. Characteristic skin lesions such as hypomelanotic macules and the central nervous system features such as the epilepsy, cortical tubers and subependymal nodules were the most common symptoms that were observed in the patients...
February 1, 2017: Clinical Neurology and Neurosurgery
https://www.readbyqxmd.com/read/28127866/rare-familial-tsc2-gene-mutation-associated-with-atypical-phenotype-presentation-of-tuberous-sclerosis-complex
#4
Jonah Fox, Shay Ben-Shachar, Shimrit Uliel, Ran Svirsky, Hirotomo Saitsu, Naomichi Matsumoto, Aviva Fattal-Valevski
Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. We describe an 18-month-old boy who presented with seizures and a single hypopigmented macule. He did not meet consensus criteria for the clinical diagnosis of TSC. Exome sequencing revealed a heterozygous TSC2 mutation (c.5138G>A (p.Arg1713His)) in the patient. This heterozygous alteration was detected in his mother as well as several other maternal family members...
January 27, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28092822/combination-of-everolimus-with-sorafenib-for-solid-renal-tumors-in-tsc2-mice-is-superior-to-everolimus-alone
#5
Jian Yang, Paulina A Samsel, Kalin Narov, Ashley Jones, Daniel Gallacher, John Gallacher, Julian R Sampson, Ming Hong Shen
Tuberous sclerosis (TSC) is an inherited tumor syndrome caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR and development of tumors in multiple organs including the kidneys. The mTOR inhibitors rapamycin and everolimus (rapalogs) have demonstrated clinical efficacy in treating TSC-associated tumors including renal angiomyolipomas. However, tumor responses are usually only partial, and regrowth occurs after drug withdrawal. TSC-associated tumors are highly vascular, and TSC patients with renal angiomyolipomas have elevated levels of circulating vascular endothelial growth factor (VEGF) A and VEGFD...
February 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28087349/combination-of-multiple-ligation-dependent-probe-amplification-and-illumina-miseq-amplicon-sequencing-for-tsc1-tsc2-gene-analyses-in-patients-with-tuberous-sclerosis-complex
#6
Nur Farrah Dila Ismail, Abdul Qawee Rani, Nik Mohd Ariff Nik Abdul Malik, Chia Boon Hock, Siti Nabilahuda Mohd Azlan, Salmi Abdul Razak, Wee Teik Keng, Lock Hock Ngu, Abdul Rashid Silawati, Nor AzniYahya, Narazah Mohd Yusoff, Teguh Haryo Sasongko, Zabidi Azhar Mohd Hussin
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder characterized by tumor growth in multiple organs and caused by mutations in either TSC1 or TSC2 genes. Because of their relatively large genomic sizes, absence of hotspots, and common type of mutations, mutation detection in TSC1 and TSC2 genes has been challenging. We devised a combination of multiple ligation-dependent probe amplification (MLPA) and amplicon sequencing (AS) to simplify the detection strategy, yet we come up with reasonably high detection rate...
January 10, 2017: Journal of Molecular Diagnostics: JMD
https://www.readbyqxmd.com/read/28079897/tsc1-expression-by-dendritic-cells-is-required-to-preserve-t-cell-homeostasis-and-response
#7
Yuechen Luo, Wenwen Li, Gang Yu, Juan Yu, Ling Han, Ting Xue, Zhina Sun, Song Chen, Chunming Fang, Chunxiao Zhao, Qing Niu, Fei Yang, Zhongchao Han, Tao Cheng, Yun Zeng, Fang Liao, Guogang Xu, Xiaoming Feng
Dendritic cells (DCs) are pivotal to the induction of adaptive T-cell immune responses. Recent evidence highlights a critical role of tuberous sclerosis complex 1 (Tsc1), a primarily upstream negative regulator of mammalian target of rapamycin (mTOR), in DC development, but whether and how Tsc1 directly regulate mature DC function in vivo remains elusive. Here we show that selective disruption of Tsc1 in DCs results in a lymphoproliferative disorder with the spontaneous activation of T cells. Tsc1 deficiency results in the activation of mTORC1-PPARγ pathway, which leads to the upregulation of neuropilin-1 (Nrp1) expression on DCs to stimulate naive T-cell proliferation...
January 12, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28065512/assessment-of-tuberous-sclerosis-complex-associated-with-renal-lesions-by-targeted-next-generation-sequencing-in-mainland-china
#8
Yi Cai, Hanzhong Li, Yushi Zhang
OBJECTIVE: To identify the TSC1 and TSC2 mutations in patients with tuberous sclerosis complex (TSC) associated with renal lesions, and to explore the relationship between genotypes and phenotypes. MATERIALS AND METHODS: We analyzed 43 individuals affected with TSC accompanied by renal lesions using next-generation sequencing (NGS). We also performed Sanger sequencing to validate the NGS results. RESULTS: We reported a comprehensive mutation analysis of 43 affected individuals with TSC accompanied by renal lesions using NGS...
January 5, 2017: Urology
https://www.readbyqxmd.com/read/28061838/cryptotanshinone-activates-ampk-tsc2-axis-leading-to-inhibition-of-mtorc1-signaling-in-cancer-cells
#9
Wenxing Chen, Yanhong Pan, Siliang Wang, Yuping Liu, Guangying Chen, Liang Zhou, Wenting Ni, Aiyun Wang, Yin Lu
BACKGROUND: Cryptotanshinone (CPT), a fat-soluble phenanthraquinone from Salvia miltiorrhiza Bunge, has been demonstrated to inhibit phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), a couple of direct downstream effectors of the mammalian target of rapamycin complex 1 (mTORC1), resulting in cancer cell arrested in G0 phase and subsequent inhibition of proliferation. However, its concrete molecular mechanism about how CPT inhibits mTORC1 signaling pathway is unclear...
January 7, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28057888/mtor-complex-1-signalling-regulates-the-balance-between-lipid-synthesis-and-oxidation-in-hypoxia-lymphocytes
#10
Geng Yin, Yan Liang, Ying Wang, Yuan Yang, Min Yang, Xiao-Min Cen, Qi-Bing Xie
Mammalian cells adapt to different environmental conditions and alter cellular metabolic pathways to meet the energy demand for survival. Thus, the metabolic regulation of cells under special conditions, such as hypoxia, should be precisely regulated. During the metabolic regulation, mammalian target of rapamycin (mTOR) plays a vital role in the sensing of extracellular stimulations and regulating intracellular adaptations. Here, we report that mTOR complex 1 (mTORC1) signalling is a central regulator of lipid homoeostasis in lymphocytes...
February 28, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28053551/genetics-of-tuberous-sclerosis-complex-implications-for-clinical-practice
#11
REVIEW
Carolina Caban, Nubaira Khan, Daphne M Hasbani, Peter B Crino
Tuberous sclerosis complex (TSC) is a multisystem disorder that results from heterozygous mutations in either TSC1 or TSC2. The primary organ systems that are affected include the brain, skin, lung, kidney, and heart, all with variable frequency, penetrance, and severity. Neurological features include epilepsy, autism, and intellectual disability. There are more than 1,500 known pathogenic variants for TSC1 and TSC2, including deletion, nonsense, and missense mutations, and all pathogenic mutations are inactivating, leading to loss of function effects on the encoded proteins TSC1 and TSC2...
2017: Application of Clinical Genetics
https://www.readbyqxmd.com/read/28043938/mtorc1-activation-downregulates-fgfr3-and-pth-pthrp-receptor-in-articular-chondrocytes-to-initiate-osteoarthritis
#12
H Zhang, H Wang, C Zeng, B Yan, J Ouyang, X Liu, Q Sun, C Zhao, H Fang, J Pan, D Xie, J Yang, T Zhang, X Bai, D Cai
OBJECTIVE: Articular chondrocyte activation, involving aberrant proliferation and prehypertrophic differentiation, is essential for osteoarthritis (OA) initiation and progression. Disruption of mechanistic target of rapamycin complex 1 (mTORC1) promotes chondrocyte autophagy and survival, and decreases the severity of experimental OA. However, the role of cartilage mTORC1 activation in OA initiation is unknown. In this study, we elucidated the specific role of mTORC1 activation in OA initiation, and identify the underlying mechanisms...
December 31, 2016: Osteoarthritis and Cartilage
https://www.readbyqxmd.com/read/28041914/repression-of-tsc1-tsc2-mediated-by-mecp2-regulates-human-embryo-lung-fibroblast-cell-differentiation-and-proliferation
#13
Yuanyuan Wang, Chen Chen, Ziyu Deng, Erbao Bian, Cheng Huang, Ting Lei, Xiongwen Lv, Liping Liu, Jun Li
Pulmonary fibrosis (PF) is a severe inflammatory disease with limited effective treatments. It is known that the transdifferentiation of human embryo lung fibroblast (HELF) cells from pulmonary fibroblasts into myofibroblasts, contributes to the progression of pulmonary fibrogenesis. The tuberous sclerosis proteins TSC1 and TSC2 are two key signaling factors which can suppress cell growth and proliferation. However, the roles of TSC1 and TSC2 in lung fibroblast are unclear. Here, we developed a PF model with bleomycin (BLM) in mice and conducted several simulation experiments in HELF cells...
December 29, 2016: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28031543/molecular-rescue-of-tsc1-ablated-cortical-tuber-mice
#14
EDITORIAL
Barbara Robens, Albert J Becker
No abstract text is available yet for this article.
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28027327/mutational-profile-of-metastatic-breast-cancers-a-retrospective-analysis
#15
Celine Lefebvre, Thomas Bachelot, Thomas Filleron, Marion Pedrero, Mario Campone, Jean-Charles Soria, Christophe Massard, Christelle Lévy, Monica Arnedos, Magali Lacroix-Triki, Julie Garrabey, Yannick Boursin, Marc Deloger, Yu Fu, Frédéric Commo, Véronique Scott, Ludovic Lacroix, Maria Vittoria Dieci, Maud Kamal, Véronique Diéras, Anthony Gonçalves, Jean-Marc Ferrerro, Gilles Romieu, Laurence Vanlemmens, Marie-Ange Mouret Reynier, Jean-Christophe Théry, Fanny Le Du, Séverine Guiu, Florence Dalenc, Gilles Clapisson, Hervé Bonnefoi, Marta Jimenez, Christophe Le Tourneau, Fabrice André
BACKGROUND: Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. METHODS AND FINDINGS: Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/28013293/deficient-tsc1-tsc2-complex-suppression-of-sox9-osteopontin-akt-signalling-cascade-constrains-tumour-growth-in-tuberous-sclerosis-complex
#16
Fuquan Jin, Keguo Jiang, Shuang Ji, Li Wang, Zhaofei Ni, Fuqiang Huang, Chunjia Li, Rongrong Chen, Hongbing Zhang, Zhongdong Hu, Xiaojun Zha
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder featured with multi-organ benign tumours. Disruption of TSC1/TSC2 complex suppression on mammalian/mechanistic target of rapamycin (mTOR) signalling causes TSC. Hyperactive mTOR-mediated negative feedback regulation of AKT partially contributes to the benign nature of TSC-associated tumours. In this study, we demonstrated that osteopontin (OPN) was dramatically reduced by loss of TSC1/TSC2 complex in Tsc2-null mouse embryonic fibroblasts (MEFs), rat uterine leiomyoma-derived Tsc2-deficient cells, genetically modified mouse TSC models, and clinical samples...
December 23, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27974549/tsc1-2-mutations-define-a-molecular-subset-of-hcc-with-aggressive-behaviour-and-treatment-implication
#17
Daniel W H Ho, Lo K Chan, Yung T Chiu, Iris M J Xu, Ronnie T P Poon, Tan T Cheung, Chung N Tang, Victor W L Tang, Irene L O Lo, Polly W Y Lam, Derek T W Yau, Miao X Li, Chun M Wong, Irene O L Ng
OBJECTIVE: We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. DESIGN: We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence...
December 14, 2016: Gut
https://www.readbyqxmd.com/read/27918305/tuberous-sclerosis-complex-inactivation-disrupts-melanogenesis-via-mtorc1-activation
#18
Juxiang Cao, Magdalena E Tyburczy, Joel Moss, Thomas N Darling, Hans R Widlund, David J Kwiatkowski
Tuberous sclerosis complex (TSC) is an autosomal dominant tumor-suppressor gene syndrome caused by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essential regulator of mTOR complex 1 (mTORC1). Patients with TSC develop hypomelanotic macules (white spots), but the molecular mechanisms underlying their formation are not fully characterized. Using human primary melanocytes and a highly pigmented melanoma cell line, we demonstrate that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1 activation, which results in hyperactivation of glycogen synthase kinase 3β (GSK3β), followed by phosphorylation of and loss of β-catenin from the nucleus, thereby reducing expression of microphthalmia-associated transcription factor (MITF), and subsequent reductions in tyrosinase and other genes required for melanogenesis...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27907099/analysis-of-a-mouse-skin-model-of-tuberous-sclerosis-complex
#19
Yanan Guo, John R Dreier, Juxiang Cao, Heng Du, Scott R Granter, David J Kwiatkowski
Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor gene syndrome in which patients develop several types of tumors, including facial angiofibroma, subungual fibroma, Shagreen patch, angiomyolipomas, and lymphangioleiomyomatosis. It is due to inactivating mutations in TSC1 or TSC2. We sought to generate a mouse model of one or more of these tumor types by targeting deletion of the Tsc1 gene to fibroblasts using the Fsp-Cre allele. Mutant, Tsc1ccFsp-Cre+ mice survived a median of nearly a year, and developed tumors in multiple sites but did not develop angiomyolipoma or lymphangioleiomyomatosis...
2016: PloS One
https://www.readbyqxmd.com/read/27906092/alterations-to-mtorc1-signaling-in-the-skeletal-muscle-differentially-affect-whole-body-metabolism
#20
Maitea Guridi, Barbara Kupr, Klaas Romanino, Shuo Lin, Denis Falcetta, Lionel Tintignac, Markus A Rüegg
BACKGROUND: The mammalian target of rapamycin complex 1 (mTORC1) is a central node in a network of signaling pathways controlling cell growth and survival. This multiprotein complex integrates external signals and affects different nutrient pathways in various organs. However, it is not clear how alterations of mTORC1 signaling in skeletal muscle affect whole-body metabolism. RESULTS: We characterized the metabolic phenotype of young and old raptor muscle knock-out (RAmKO) and TSC1 muscle knock-out (TSCmKO) mice, where mTORC1 activity in skeletal muscle is inhibited or constitutively activated, respectively...
March 21, 2016: Skeletal Muscle
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